Glycopeptide derivative compounds and uses thereof

ABSTRACT

Provided herein are methods and compositions for the treatment of Gram positive bacterial infections. The infection in some embodiments, is a pulmonary infection. The method for treating the bacterial infection, comprises in one embodiment, administering to a patient in need thereof, a composition comprising an effective amount of a compound a glycopeptide derivative of Formula (I) or (II), or a pharmaceutically acceptable salt of Formula (I) or (II).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional Application Ser.No. 62/509,378, filed May 22, 2017; U.S. Provisional Application Ser.No. 62/518,280, filed Jun. 12, 2017; and U.S. Provisional ApplicationSer. No. 62/560,413, filed Sep. 19, 2017, the disclosures of each ofwhich is incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

The high frequency of multidrug resistant bacteria, and in particular,Gram-positive bacteria, both in the hospital setting and the communitypresent a significant challenge for the management of infections (Krauseet al. (2008). Antimicrobial Agents and Chemotherapy 52(7), pp.2647-2652, incorporated by reference herein in its entirety for allpurposes).

The treatment of invasive Staphylococcus aureus (S. aureus) infectionshas relied significantly on vancomycin. However, the treatment andmanagement of such infections is a therapeutic challenge because certainS. aureus isolates, and in particular, methicillin-resistant S. aureusisolates, have been shown to be resistant to vancomycin (Shaw et al.(2005). Antimicrobial Agents and Chemotherapy 49(1), pp. 195-201; Mendeset al. (2015). Antimicrobial Agents and Chemotherapy 59(3), pp.1811-1814, each of which is incorporated by reference herein in itsentirety for all purposes).

Because of the resistance displayed by many Gram-positive organisms toantibiotics, and the general lack of susceptibility to existingantibiotics, there is a need for new therapeutic strategies to combatinfections due to these bacteria. The present invention addresses thisand other needs.

SUMMARY OF THE INVENTION

In one aspect of the invention, a method is provided for treating abacterial infection in a patient in need thereof. In one aspect a methodof the invention comprises administrating to the patient a compositioncomprising an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof:

-   -   wherein,

R¹ is C₁-C₁₈ linear alkyl, C₁-C₁₈ branched alkyl, R⁵—Y—R⁶—(Z)_(n), or

R² is —OH or —NH—(CH₂)_(q)—R⁷;

R³ is H or

R⁴ is H or CH₂—NH—CH₂—PO₃H₂;

n is 1 or 2;

each q is independently 1, 2, 3, 4, or 5;

X is O, S, NH or H₂;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

R⁵ and R⁶ are independently selected from the group consisting ofalkylene, alkenylene and alkynylene, wherein the alkylene, alkenyleneand alkynylene groups are optionally substituted with from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl

R⁷ is —N(CH₂)₂; —N⁺(CH₂)₃; or

Y is independently selected from the group consisting of oxygen, sulfur,—S—S—, —NR⁸—, —S(O)—, —SO₂—, —NR⁸C(O)—, —OSO₂—, —OC(O)—, —NR⁸SO₂—,—C(O)NR⁸—, —C(O)O—, —SO₂NR⁸—, —SO₂O—, —P(O)(OR⁸)O—, —P(O)(OR⁸)NR⁸—,—OP(O)(OR⁸)O—, —OP(O)(OR⁸)NR⁸—, —OC(O)O—, —NR⁸C(O)O—, —NR⁸C(O)NR⁸—,—OC(O)NR⁸— and —NR⁸SO₂NR⁸—; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.

In another aspect, a method of the invention comprises administrating tothe patient a composition comprising an effective amount of a compoundof Formula (II), a prodrug thereof, or a pharmaceutically acceptablesalt thereof:

-   -   wherein,

R¹ is C₁-C₁₈ linear alkyl, C₁-C₁₈ branched alkyl, R⁵—Y—R⁶—(Z)_(n), or

R² is —OH or —NH—(CH₂)_(q)—R⁷;

R³ is H or

R⁴ is H or CH₂—NH—CH₂—PO₃H₂;

n is 1 or 2;

each q is independently 1, 2, 3, 4, or 5;

X is O, S, NH or H₂;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

R⁵ and R⁶ are independently selected from the group consisting ofalkylene, alkenylene and alkynylene, wherein the alkylene, alkenyleneand alkynylene groups are optionally substituted with from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl;

R⁷ is —N(CH₂)₂; —N⁺(CH₂)₃; or

Y is independently selected from the group consisting of oxygen, sulfur,—S—S—, —NR⁸—, —S(O)—, —SO₂—, —OSO₂—, —NR⁸SO₂—, —SO₂NR⁸—, —SO₂O—,—P(O)(OR⁸)O—, —P(O)(OR⁸)NR⁸—, —OP(O)(OR⁸)O—, —OP(O)(OR⁸)NR⁸—,—NR⁸C(O)NR⁸—, and —NR⁸SO₂NR⁸—; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.

In one embodiment of the method for treating a bacterial infection, thecomposition comprises an effective amount of a compound of Formula (I),Formula (II), or a pharmaceutically acceptable salt of Formula (I) orFormula (II), wherein R¹ is C₆ to C₁₆ linear alkyl. In a furtherembodiment, R¹ is C₆, C₁₀ or C₁₆ alkyl. In even a further embodiment, Ris C₁₀ alkyl. In a further embodiment, the bacterial infection is apulmonary bacterial infection. In even a further embodiment, theadministering comprises administering via inhalation.

In one embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ is R⁵—Y—R⁶—(Z)_(n). In a furtherembodiment, R⁵ is —(CH₂)₂—, R⁶ is —(CH₂)₁₀—, X is O; Y is NR⁸, Z ishydrogen and n is 1. In a further embodiment, R⁸ is hydrogen. As such,one embodiment of the invention includes a compound of Formula (I),Formula (II) or a pharmaceutically acceptable salt thereof, where R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃. In a further embodiment, the bacterial infectionis a pulmonary bacterial infection. In even a further embodiment, theadministering comprises administering via inhalation.

In one embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃ and R³and R⁴ are H. In a further embodiment, R² is OH. In even a furtherembodiment, the administering comprises administering via theintravenous route. In a further embodiment, X is O.

In one embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II) where R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃, R² is—NH—(CH₂)_(q)—R⁷, and R³ and R⁴ are H. In a further embodiment, theadministering comprises administering via the intravenous or pulmonaryroute. In even a further embodiment, q is 2 or 3 and R⁷ is —N(CH₂)₂. Ina further embodiment, X is O.

In one embodiment of the methods provided herein, the compositionadministered to the patient comprises an effective amount of a compoundof Formula (I) or Formula (II), where R¹ is

In a further embodiment, R² is OH and R³ and R⁴ are H. In even a furtherembodiment, the halogen is Cl and q is 1 or 2. In a further embodiment,the administering comprises administering via the pulmonary orintravenous route. In a further embodiment, X is O and R¹ is

In one embodiment of the methods provided herein, the compositionadministered to the patient comprises an effective amount of a compoundof Formula (I) or Formula (II), where R¹ is

R² is OH and R³ is

and R⁴ is H. In even a further embodiment, the halogen is Cl and q is 1or 2. In a further embodiment, the administering comprises administeringvia the intravenous route. In a further embodiment, X is O and R¹ is

In yet another embodiment, the bacterial infection is a Gram-positivecocci infection and the composition administered to the patient in needthereof comprises an effective amount of a compound of Formula (I),Formula (II), or a pharmaceutically acceptable salt of Formula (I) orFormula (II), wherein R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃. In a furtherembodiment, the infection is a Gram-positive infection is a cocciinfection, and in a further embodiment, is a vancomycin-resistantenterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA),methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycinresistant Enterococcus faecium also resistant to teicoplanin (VRE Fm VanA), vancomycin resistant Enterococcus faecium sensitive to teicoplanin(VRE Fm Van B), vancomycin resistant Enterococcus faecalis alsoresistant to teicoplanin (VRE Fs Van A), vancomycin resistantEnterococcus faecalis sensitive to teicoplanin (VRE Fs Van B), orpenicillin-resistant Streptococcus pneumoniae (PRSP).

In even another embodiment, the bacterial infection is a Gram-positivecocci infection and the composition administered to the patient in needthereof comprises an effective amount of a compound of Formula (I),Formula (II), or a pharmaceutically acceptable salt of Formula (I) orFormula (II), wherein R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃. In a furtherembodiment, the infection is erythromycin-resistant (erm^(R)),vancomycin-intermediate S. aureus (VISA) heterogenousvancomycin-intermediate S. aureus (hVISA), S. epidermidiscoagulase-negative staphylococci (CoNS), penicillin-intermediate S.pneumoniae (PISP), or penicillin-resistant S. pneumoniae (PRSP).

In even another embodiment, R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃ and thebacterial infection is Propionibacterium acnes (skin acne), Eggerthellalenta (bacteremia) or Peptostreptococcus anaerobius (gynecologicalinfection). In a further embodiment, R² is OH and R³ and R⁴ are H.

In one embodiment, the bacterial infection is a methicillin-resistantStaphylococcus aureus (MRSA) infection and the composition administeredto the patient in need thereof comprises an effective amount of acompound of Formula (I), Formula (II), or a pharmaceutically acceptablesalt of Formula (I) or Formula (II), wherein R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃. In a further embodiment, the administration isconducted via a nebulizer or a dry powder inhaler and the bacterialinfection is a pulmonary infection. In another embodiment,administration is intravenous, R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃; R² is OH andR³ and R⁴ are H. In a further embodiment, X is O.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1, top shows the reductive amination of vancomycin to arrive at aglycopeptide derivative. The reaction occurs at the primary amine ofvancomycin. FIG. 1, bottom, shows a synthesis scheme for achloroeremomycin derivative.

FIG. 2 shows synthesis schemes for making the glycopeptide derivativeRV40.

FIG. 3 shows a synthesis scheme for making the glycopeptide derivativeRV79.

FIG. 4 is a synthesis scheme for making alkyl vancomycin derivatives.

FIG. 5 shows one synthesis scheme for making decyl-vancomycin (Compound#5).

FIG. 6 is a bar graph showing the minimum inhibitory concentration (MIC)(μg antibiotic/mL) for various antibiotics against 23 different S.aureus strains.

FIG. 7 is a scatter plot showing the minimum inhibitory concentration(MIC) (μg antibiotic/mL) for various antibiotics against 23 different S.aureus strains. Data is plotted as geometric mean with a 95% confidenceinterval.

FIG. 8 is a bar graph showing the minimum inhibitory concentration (MIC)(μg antibiotic/mL) for various antibiotics against 12 different MRSAstrains.

FIG. 9 is a scatter plot showing the minimum inhibitory concentration(MIC) (μg antibiotic/mL) for various antibiotics against 12 differentMRSA strains. Data is plotted as geometric mean with a 95% confidenceinterval.

FIG. 10 is a graph showing the log reduction of in CFU/mL biofilm as afunction of antibiotic concentration (μg/mL).

FIG. 11 is a graph showing the log reduction of in CFU/mL biofilm as afunction of antibiotic concentration (μg/mL).

FIG. 12 is a graph showing bacterial burden in lung versus control inanimal model of pulmonary MRSA infection. Dose based on body weighttarget. The geometric mean for control was 6.4 Log₁₀ CFU/g lung versus3.2 Log₁₀ CFU/g lung for RV40 treatment. Error is 95% Cl of geometricmean. N=11 for control and n=10 for RV40 treatment. P<0.0001,Mann-Whitney U-Test.

FIG. 13 is a graph showing the difference in log reduction in CFU/g lungversus control treatment (nebulized inhaled saline) for variousantibiotics. Dose based on body weight target. Data plotted as mean oflog values and error is SEM. Vehicle and control for RV40 and ORI wasbicine buffer, pH 9.2. Vehicle and control for Vancomycin treatments wassaline. N=10 for RV40, n=11 for ORI, n=9 for VAN neb, and n=6 for VANi.v.

FIG. 14 is a graph showing reduction in lung CFU for inhaled RV40targeted delivered dosed at 10, 5, 2, and 1 mg/kg vs control. Drugs wereadministered via inhalation at 12 and 24 h after intranasal bacterialchallenge with MRSA (USA300, ATCC BAA-1556) in neutropenic rats and CFUswere counted 36 h after challenge. Data plotted is average of Log CFU/g(n=10 for 10 mg/kg, n=9 for 5 and 2 mg/kg, and n=11 for 1 mg/kg groups).Error is SEM.

FIG. 15 is a graph showing the difference in log reduction in CFU/g lungversus control treatment (nebulized inhaled saline) for prophylacticdosing of RV40. Prophylactic dosing of inhaled RV40 reduces lungbacterial burden vs. control (inhaled saline) up to 5 days beforeinfection. Single doses of RV40 (10 mg/kg delivered target) wereadministered by inhalation. Neutropenic rats were infected with MRSA(USA300, ATCC BAA-1556) on Day 0 and CFUs were counted 36 h afterchallenge. Data plotted as geometric mean of CFU/g. Error bars are 95%confidence interval (CI). Statistics based on one-way ANOVA (p=0.001)with post-hoc Bonferroni multiple comparison test. N=11 for treatmentgroups on Days −7, −5, −3, −1, n=10 for Day +0.5, and n=8 for control.

DETAILED DESCRIPTION OF THE INVENTION

The high frequency of multidrug resistant bacteria, and in particular,Gram-positive bacteria, both in the healthcare setting and the communitypresent a significant challenge for the management of infections (Krauseet al. (2008). Antimicrobial Agents and Chemotherapy 52(7), pp.2647-2652, incorporated by reference herein in its entirety for allpurposes). Moreover, methicillin resistant S. aureus (MRSA) infectionsin cystic fibrosis (CF) patients is a concern, and there is a lack ofclinical data regarding approaches to eradicate such infections (Gossand Muhlebach (2011). Journal of Cystic Fibrosis 10, pp. 298-306,incorporated by reference herein in its entirety for all purposes).

The present invention addresses the need for new bacterial infectiontreatment methods, and in particular, bacterial infection treatmentmethods by delivering compounds of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II) topatients in need thereof, for example via the pulmonary or intravenousroute.

In one aspect, the present invention relates to methods for treatingbacterial infections, for example, Gram-positive bacterial infectionsand in some embodiments, Gram-positive bacterial pulmonary infections.The method, in one embodiment, comprises administering to a patient inneed thereof, a composition comprising an effective amount of a compoundof Formula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II). The composition can be administered by anyroute. In the case of a pulmonary infection, in one embodiment, thecomposition is administered via a nebulizer, dry powder inhaler ormetered dose inhaler. In another embodiment, the composition isadministered intravenously.

The compounds for use in the bacterial infection treatment methods, andthe specific treatment methods, are discussed in detail below.

An “effective amount” of a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), is anamount that can provide the desired therapeutic response. The effectiveamount can refer to a single dose as part of multiple doses during anadministration period, or as the total dosage of glycopeptide givenduring an administration period. A treatment regimen can includesubstantially the same dose for each glycopeptide administration, or cancomprise at least one, at least two or at least three different dosages.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 40 carbon atoms, e.g., from1 to 10 carbon atoms, or from 1 to 6 carbon atoms. This term isexemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like. Bothlinear and branched alkyl groups are encompassed by the term “alkyl”.

The term “substituted alkyl” refers to an alkyl group as defined above,having from 1 to 8 substituents, e.g., from 1 to 5 substituents or from1 to 3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO— heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, for example, having from 1 to 40 carbonatoms, e.g., from 1 to 10 carbon atoms, or from 1 to 6 carbon atoms.This term is exemplified by groups such as methylene (CH₂—), ethylene(—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CCH₂—)and the like.

The term “substituted alkylene” refers to an alkylene group, as definedabove, having from 1 to 5 substituents, for example, from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl.Additionally, such substituted alkylene groups include those where 2substituents on the alkylene group are fused to form one or morecycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to thealkylene group. Such fused groups can contain from 1 to 3 fused ringstructures. Additionally, the term substituted alkylene includesalkylene groups in which from 1 to 5 of the alkylene carbon atoms arereplaced with oxygen, sulfur or NR— where R is hydrogen or alkyl.Examples of substituted alkylenes are chloromethylene (—CH(Cl)—),aminoethylene (—CH(NH₂)CH₂—), 2-carboxypropylene isomers(—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂—O—CH₂CH₂—) and the like.

The term “alkaryl” refers to the groups -alkylene-aryl and substitutedalkylene-aryl where alkylene, substituted alkylene and aryl are definedherein. Such alkaryl groups are exemplified by benzyl, phenethyl and thelike.

The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O-cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Alkyl-O—alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

The term “substituted alkoxy” refers to the groups substituted alkyl-O—,substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O— where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein.

The term “alkylalkoxy” refers to the groups -alkylene-O-alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Alkylalkoxy groups are also expressed as alkylene-O-alkyl and include,by way of example, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy(—CH₂CH₂OCH₃), n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂),methylene-t-butoxy (—CH₂—O—C(CH₃)₃) and the like.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 40 carbon atoms, e.g., 2to 10 carbon atoms or 2 to 6 carbon atoms, and having at least 1 and insome embodiments, from 1-6 sites of vinyl unsaturation. Alkenyl groupsinclude ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), iso-propenyl(—C(CH₃)═CH₂), and the like.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having from 1 to 5 substituents, and e.g., from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkenylene” refers to a diradical of a branched or unbranchedunsaturated hydrocarbon group having from 2 to 40 carbon atoms, forexample from 2 to 10 carbon atoms or from 2 to 6 carbon atoms and havingat least 1 and for example, from 1-6 sites of vinyl unsaturation. Thisterm is exemplified by groups such as ethenylene (—CH═CH—), thepropenylene isomers (e.g., —CH₂CH═CH— and —C(CH₃)═CH—) and the like.

The term “substituted alkenylene” refers to an alkenylene group asdefined above having from 1 to 5 substituents, and for example, from 1to 3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO— heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl. Additionally, such substituted alkenylene groupsinclude those where 2 substituents on the alkenylene group are fused toform one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fusedto the alkenylene group.

The term “alkynyl” refers to a monoradical of an unsaturated hydrocarbonhaving from 2 to 40 carbon atoms, for example, from 2 to 20 carbonatoms, or from 2 to 6 carbon atoms and having at least 1 and in someembodiments from 1 to 6 sites of acetylene (triple bond) unsaturation.Representative alkynyl groups include ethynyl (—C≡CH), propargyl(—CH₂C≡CH) and the like.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having from 1 to 5 substituents, for example, from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon having from 2 to 40 carbon atoms, for example from 2 to 10carbon atoms or 2 to 6 carbon atoms and having at least 1 and in someembodiment, from 1-6 sites of acetylene (triple bond) unsaturation.Representative alkynylene groups include ethynylene (—C≡C—),propargylene (—CH₂C≡C—).

The term “substituted alkynylene” refers to an alkynylene group asdefined above having from 1 to 5 substituents, for example, from 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO— heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,heteroaryl-C(O)— and heterocyclic-C(O)— where alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “acylamino” or “aminocarbonyl” refers to the group —C(O)NRRwhere each R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, heterocyclic or where both R groups are joined to form aheterocyclic group (e.g., morpholino) wherein alkyl, substituted alkyl,aryl, heteroaryl and heterocyclic are as defined herein.

The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

The term “aminoacyloxy” or “alkoxycarbonylamino” refers to the group—NRC(O)OR where each R is independently hydrogen, alkyl, substitutedalkyl aryl, heteroaryl, or heterocyclic.

The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic group offrom 6 to 20 carbon atoms having a single ring (e.g., phenyl) ormultiple condensed (fused) rings (e.g., naphthyl or anthryl).Representative aryls include phenyl, naphthyl and the like. Unlessotherwise constrained by the definition for the aryl substituent, sucharyl groups can optionally be substituted with from 1 to 5 substituents,e.g., from 1 to 3 substituents, selected from the group consisting ofacyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy,substituted alkenyl, substituted alkynyl, substituted cycloalkyl,substituted cycloalkenyl, amino, substituted amino, aminoacyl,acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl,cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, aminoacyloxy, oxyacylamino, sulfonamide, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl. Inone embodiment, the aryl substituent is alkyl, alkoxy, halo, cyano,nitro, trihalomethyl, thioalkoxy or a combination thereof.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above including optionally substituted aryl groups as alsodefined above.

The term “arylene” refers to the diradical derived from aryl (includingsubstituted aryl) as defined above and is exemplified by 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic provided thatboth R groups are not H.

“Amino acid” refers to any of the naturally occurring amino acids,synthetic amino acids, and derivatives thereof α-Amino acids comprise acarbon atom to which is bonded an amino group, a carboxy group, ahydrogen atom, and a distinctive group referred to as a “side chain”.The side chains of naturally occurring amino acids are well known in theart and include, for example, hydrogen (e.g., glycine), alkyl (e.g.,alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g.,as in threonine, serine, methionine, cysteine, aspartic acid,asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl(e.g., phenylalanine and tryptophan), substituted arylalkyl (e.g.,tyrosine), and heteroarylalkyl (e.g., histidine).

The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O-cycloalkyl”,“—C(O)O-substituted cycloalkyl”, “—C(O)O— alkenyl”, “—C(O)O-substitutedalkenyl”, “—C(O)O-alkynyl” and “—C(O)O-substituted alkynyl” where alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl are as definedherein

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups havingfrom 1 to 5 substituents, and for example, from 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “cycloalkenyl” refers to cyclic alkenyl groups of from 4 to 20carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,e.g., cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl.

The term “substituted cycloalkenyl” refers to cycloalkenyl groups havingfrom 1 to 5 substituents, and for example, from 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

The term “halo” or “halogen” refers to fluoro, chloro, bromo and/oriodo.

“Haloalkyl” refers to alkyl as defined herein substituted by 1-4 halogroups as defined herein, which may be the same or different.Representative haloalkyl groups include, by way of example,trifluoromethyl, 3-fluorododecyl, 12,12,12-trifluorododecyl,2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term “heteroaryl” refers to an aromatic group of from 1 to 15 carbonatoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfurwithin at least one ring moiety.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, for example from 1 to 3 substituents, selected fromthe group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl and trihalomethyl.Representative aryl substituents include alkyl, alkoxy, halo, cyano,nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have asingle ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). In one embodiment, the heteroaryl ispyridyl, pyrrolyl or furyl. “Heteroarylalkyl” refers to(heteroaryl)alkyl- where heteroaryl and alkyl are as defined herein.Representative examples include 2-pyridylmethyl and the like.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heteroarylene” refers to the diradical group derived fromheteroaryl (including substituted heteroaryl), as defined above, and isexemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl and the like.

The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated unsaturated group having a single ring or multiple condensedrings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, forexample from 1 to 4 heteroatoms, selected from nitrogen, sulfur,phosphorus, and/or oxygen within the ring.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5, and for example, from 1 to 3 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Suchheterocyclic groups can have a single ring or multiple condensed rings.In one embodiment, the heterocyclic is morpholino or piperidinyl.

Examples of nitrogen heterocycles and heteroaryls include, but are notlimited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

Another class of heterocyclics is known as “crown compounds” whichrefers to a specific class of heterocyclic compounds having one or morerepeating units of the formula [(CH₂—)_(a)A-] where a is equal to orgreater than 2, and A at each separate occurrence can be 0, N, S or P.Examples of crown compounds include, by way of example only,[—(CH₂)₃—NH-]3, [—((CH₂)₂—O)₄—((CH₂)₂—NH)₂] and the like. In oneembodiment, the crown compound has from 4 to 10 heteroatoms and 8 to 40carbon atoms.

The term “heterocyclooxy” refers to the group heterocyclic-O—.

The term “heterocyclene” refers to the diradical group formed from aheterocycle, as defined herein, and is exemplified by the groups2,6-morpholino, 2,5-morpholino and the like.

The term “oxyacylamino” or “aminocarbonyloxy” refers to the group—OC(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “spiro-attached cycloalkyl group” refers to a cycloalkyl groupattached to another ring via one carbon atom common to both rings.

The term “sulfonamide” refers to a group of the formula —SO₂NRR, whereeach R is independently hydrogen, alkyl, substituted alkyl, aryl,heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl,heteroaryl and heterocyclic are as defined herein.

The term “thiol” refers to the group —SH.

The term “thioheteroaryloxy” refers to the group heteroaryl-S— whereinthe heteroaryl group is as defined above including optionallysubstituted aryl groups as also defined above.

As to any of the above groups which contain one or more substituents, itis understood that such groups do not contain any substitution orsubstitution patterns which are sterically impractical and/orsynthetically non-feasible. In addition, the compounds of this inventioninclude all stereochemical isomers arising from the substitution ofthese compounds.

“Glycopeptide” refers to heptapeptide antibiotics, characterized by amulti-ring peptide core optionally substituted with saccharide groups.Examples of glycopeptides included in this definition may be found in“Glycopeptides Classification, Occurrence, and Discovery”, by Raymond C.Rao and Louise W. Crandall, (“Drugs and the Pharmaceutical Sciences”Volume 63, edited by Ramakrishnan Nagarajan, published by Marcal Dekker,Inc.), which is hereby incorporated by reference in its entirety.Representative glycopeptides include those identified as A477, A35512,A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65,Actaplanin, Actinoidin, Ardacin, Avoparcin, Azureomycin, Balhimycin,Chloroorientiein, Chloropolysporin, Decaplanin, N-demethylvancomycin,Eremomycin, Galacardin, Helvecardin, Izupeptin, Kibdelin, LL-AM374,Mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260,MM55266, MM55270, MM56597, MM56598, OA-7653, Orenticin, Parvodicin,Ristocetin, Ristomycin, Synmonicin, Teicoplanin, Telavancin, UK-68597,UK-69542, UK-72051, Vancomycin, and the like. The term “glycopeptide” asused herein is also intended to include the general class of peptidesdisclosed above on which the sugar moiety is absent, i.e., the aglyconeseries of glycopeptides. For example, removal of the disaccharide moietyappended to the phenol on vancomycin by mild hydrolysis gives vancomycinaglycone. Also within the scope of the invention are glycopeptides thathave been further appended with additional saccharide residues,especially aminoglycosides, in a manner similar to vancosamine. Inembodiments described herein, one or more of the aforementionedglycopeoptides can be used in combination with a compound of Formula(I), Formula (II), or a pharmaceutically acceptable salt of Formula (I)or (II).

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable addition salt refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid (HCl), hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid (e.g., as lactate), lactobionic acid,lauric acid, maleic acid, malic acid, malonic acid, mandelic acid,methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, aceticacid (e.g., as acetate), tartaric acid, thiocyanic acid,p-toluenesulfonic acid, trifluoroacetic acid (TFA), undecylenic acid,and the like. In one embodiment, the pharmaceutically acceptable salt isHCl, TFA, lactate or acetate.

A pharmaceutically acceptable base addition salt retains the biologicaleffectiveness and properties of the free acids, which are notbiologically or otherwise undesirable. These salts are prepared fromaddition of an inorganic base or an organic base to the free acid. Saltsderived from inorganic bases include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum salts and the like. Inorganic salts includethe ammonium, sodium, potassium, calcium, and magnesium salts. Saltsderived from organic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as ammonia, isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, diethanolamine,ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine,glucosamine, methylglucamine, theobromine, triethanolamine,tromethamine, purines, piperazine, piperidine, N-ethylpiperidine,polyamine resins and the like. Organic bases that can be used to form apharmaceutically acceptable salt include isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

In one aspect of the invention, a method is provided for treating abacterial infection in a patient in need thereof. The method comprisesadministrating to the patient a composition comprising an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

-   -   wherein,

R¹ is C₁-C₁₈ linear alkyl, C₁-C₁₈ branched alkyl, R⁵—Y—R⁶—(Z)_(n), or

R² is —OH or —NH—(CH₂)_(q)—R⁷;

R³ is H or

R⁴ is H or CH₂—NH—CH₂—PO₃H₂;

n is 1 or 2;

each q is independently 1, 2, 3, 4, or 5;

X is O, S, NH or H₂;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

R⁵ and R⁶ are independently selected from the group consisting ofalkylene, alkenylene and alkynylene, wherein the alkylene, alkenyleneand alkynylene groups are optionally substituted with from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl

R⁷ is —N(CH₂)₂; —N⁺(CH₂)₃; or

Y is independently selected from the group consisting of oxygen, sulfur,—S—S—, —NR⁸—, —S(O)—, —SO₂—, —NR⁸C(O)—, —OSO₂—, —OC(O)—, —NR⁸SO₂—,—C(O)NR⁸—, —C(O)O—, —SO₂NR⁸—, —SO₂O—, —P(O)(OR⁸)O—, —P(O)(OR⁸)NR⁸—,—OP(O)(OR⁸)O—, —OP(O)(OR⁸)NR⁸—, —OC(O)O—, —NR⁸C(O)O—, —NR⁸C(O)NR⁸—,—OC(O)NR⁸— and —NR⁸SO₂NR⁸—; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic

Another aspect of the invention relates to a method of treating apatient for a bacterial infection. The method comprises administering acomposition comprising an effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof, to the patient inneed of treatment. Formula (II) is defined as follows:

-   -   wherein,

R¹ is C₁-C₁₈ linear alkyl, C₁-C₁₈ branched alkyl, R⁵—Y—R⁶—(Z)_(n), or

R² is —OH or —NH—(CH₂)_(q)—R⁷;

R³ is H or

R⁴ is H or CH₂—NH—CH₂—PO₃H₂;

n is 1 or 2;

each q is independently 1, 2, 3, 4, or 5;

X is O, S, NH or H₂;

each Z is independently selected from hydrogen, aryl, cycloalkyl,cycloalkenyl, heteroaryl and heterocyclic;

R⁵ and R⁶ are independently selected from the group consisting ofalkylene, alkenylene and alkynylene, wherein the alkylene, alkenyleneand alkynylene groups are optionally substituted with from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxy aminoacyl, azido, cyano, halogen, hydroxyl,carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl

R⁷ is —N(CH₂)₂; —N⁺(CH₂)₃; or

Y is independently selected from the group consisting of oxygen, sulfur,—S—S—, —NR⁸—, —S(O)—, —SO₂—, —OSO₂—, —NR⁸SO₂—, —SO₂NR⁸—, —SO₂O—,—P(O)(OR⁸)O—, —P(O)(OR⁸)NR⁸—, —OP(O)(OR⁸)O—, —OP(O)(OR⁸)NR⁸—,NR⁸C(O)NR¹—, and —NR⁸SO₂NR⁸—; and

each R⁸ is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, heteroaryl and heterocyclic.

Compounds of Formula (I) and Formula (II) are synthesized, in oneembodiment, by the methods provided in U.S. Pat. Nos. 6,455,669 and/or7,160,984, the disclosure of each of which is incorporated by referenceherein in their entireties. Further synthesis methods are provided inthe Example section, herein. Other preparation steps and methods thatcan be employed are disclosed in U.S. Pat. No. 6,392,012; U.S. PatentApplication Publication No. 2017/0152291; U.S. Patent ApplicationPublication No. 2016/0272682, each of which is hereby incorporated byreference in their entirety for all purposes. Methods described inInternational Publication No. WO 2018/08197, the disclosure of which isincorporated by reference in its entirety, can also be employed.Synthesis schemes are also provided at the Example section, herein.

In one embodiment, compounds of Formula (I) and Formula (II), e.g.,where R¹ is

and R² is OH, are synthesized according to the methods provided in U.S.Patent Application Publication No. 2017/0152291, the disclosure of whichis incorporated by reference in its entirety.

In embodiments, where R² is —NH—(CH₂)_(q)—R⁷, the amide coupling can becarried out as described in Yarlagadda et al. (2014). J. Med. Chem. 57,pp. 4558-4568, the disclosure of which is incorporated by referenceherein in its entirety for all purposes. For example, a solution ofvancomycin or other glycopeptide derivative (e.g., a compound of Formula(I) or Formula (II), where R¹ is

and X is O) can be treated with a solution of —NH—(CH₂)_(q)—R⁷ (e.g., asolution of —NH—(CH₂)₃—N(CH₂)₂, —NH—(CH₂)₃—N⁺(CH₂)₃, or

N-methylmorpholine and HBTU at 25° C. The reaction mixture can bestirred at 25° C. for 5 min and quenched with the addition of 50% MeOHin H₂O at 25° C. The mixture can be purified by semi-preparativereverse-phase HPLC to afford the compound as a white film.

In one embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ does not include a physiologicallycleavable functional group. Stated another way, the R¹ group, in oneembodiment, is not subject to hydrolysis or enzymatic cleavage in vivo.

In another embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ does not include an amide or estermoiety.

In one embodiment, the method for treating a bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ is R⁵—Y—R⁶—(Z)_(n). In a furtherembodiment, R⁵ is —(CH₂)₂—, R⁶ is —(CH₂)₁₀—, X is O, Y is NR, Z ishydrogen and n is 1. In a further embodiment, R⁸ is hydrogen. As such,one embodiment of the method provided herein includes delivering to apatient a composition comprising an effective amount of a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃. In afurther embodiment, X is O, R² is OH and R³ and R⁴ are H. In even afurther embodiment, administration is via the intravenous or pulmonaryroute.

In one embodiment of the method, a patient is administered a compositioncomprising an effective amount of a compound of Formula (I), Formula(II), or a pharmaceutically acceptable salt of Formula (I) or Formula(II), where R¹ is —CH₂—NH—(CH₂)₁₀—CH₃. In a further embodiment, X is O,R² is OH and R³ and R⁴ are H. In even a further embodiment,administration is via the intravenous or pulmonary route.

In one embodiment of the method, a patient is administered a compositioncomprising an effective amount of a compound of Formula (I), Formula(II), or a pharmaceutically acceptable salt of Formula (I) or Formula(II), or a pharmaceutically acceptable salt thereof, where R¹ is—(CH₂)₂—NH—(CH₂)₁₀—CH₃. In a further embodiment, X is O, R² is OH and R³and R⁴ are H. In even a further embodiment, administration is via theintravenous or pulmonary route.

In one embodiment of the method, a patient is administered a compositioncomprising an effective amount of a compound of Formula (I), Formula(II), or a pharmaceutically acceptable salt of Formula (I) or Formula(II), where R¹ is —(CH₂)₂—NH—(CH₂)₁₁—CH₃. In a further embodiment, X isO, R² is OH and R³ and R⁴ are H. In even a further embodiment,administration is via the intravenous or pulmonary route.

In another embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isadministered to the patient in need thereof, where R¹ is

X is O or H₂; and R² is —NH—(CH₂)_(q)—R⁷. In a further embodiment, R² is—NH—(CH₂)₃—R⁷. In a further embodiment, R¹ is

and R⁷ is —N⁺(CH₂)₃ or —N(CH₂)₂.

In yet another embodiment, R is C₁₀-C₁₆ alkyl. In even a furtherembodiment, R¹ is C₁₀ alkyl.

In yet another embodiment, a composition comprising an effective amountof a compound of Formula (I), Formula (II), or a pharmaceuticallyacceptable salt of Formula (I) or Formula (II), is delivered to thepatient, where R² is OH, R³ and R⁴ are H and X is O. In a furtherembodiment, R¹ is

or R⁵—Y—R⁶—(Z)_(n). In even a further embodiment, R¹ is R⁵—Y—R⁶—(Z)₁, R⁵is methylene, ethylene or propylene; R⁶ is —(CH₂)₉—, —(CH₂)₁₀—,—(CH₂)₁₁—, or —(CH₂)₁₂—, Z is H and n is 1.

In yet another embodiment, of the bacterial infection treatment methods,an effective amount of a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II) isprovided, wherein one or more hydrogen atoms is replaced with adeuterium atom.

In one embodiment, the method for treating the bacterial infectioncomprises administering to the patient in need thereof, a compound ofFormula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), where R¹ is R⁵—Y—R⁶—(Z)_(n). In a furtherembodiment, R⁵ is —(CH₂)₂—, R⁶ is —(CH₂)₁₀—, Y is NR⁸, Z is hydrogen andn is 1. In a further embodiment, R⁸ is hydrogen.

In one embodiment of the methods provided herein, R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃.

Exemplary embodiments of the compound of Formula (I) or Formula (II),for use in methods of treating bacterial infections, are provided inTable 1, below. It should be noted that the compound can also beprovided as a pharmaceutically acceptable salt. The compounds in Table 1are identified by their respective R¹, R² and X groups. Compounds ofTable 1, in one embodiment, are defined as having R³ and R⁴ as both H.In another embodiment, a compound of Table 1 is administered, where R³is

and R⁴ is H. In yet another embodiment, a compound of Table 1 isadministered, where R³ is H and R⁴ is CH₂—NH—CH₂—PO₃H₂. In even anotherembodiment, a compound of Table 1 is administered, where R³ is

and R⁴ is CH₂—NH—CH₂—PO₃H₂.

TABLE 1 Exemplary compounds of Formula (I) or Formula (II) for use withthe invention. Com- pound # R² X R¹  1. OH O —(CH₂)₅—CH₃ (n-hexyl)  2.OH O —(CH₂)₆—CH₃ (n-heptyl)  3. OH O —(CH₂)₇—CH₃ (n-octyl)  4. OH O—(CH₂)₈—CH₃ (n-nonyl)  5. OH O —(CH₂)₉—CH₃ (n-decyl)  6. OH O—(CH₂)₁₀—CH₃ (n-undecyl)  7. OH O —(CH₂)₁₁—CH₃ (n-dodecyl)  8. OH O—(CH₂)₁₂—CH₃ (n-tridecyl)  9. OH O —(CH₂)₁₃—CH₃ (n-butadecyl)  10. OH O—(CH₂)₁₄—CH₃ (n-pentadecyl)  11. OH O —(CH₂)₁₅—CH₃ (n-hexadecyl)  12. OHO —(CH₂)₁₆—CH₃ (n-heptadecyl)  13. OH O —(CH₂)₁₇—CH₃ (n-octadecyl)  14.OH O —CH₂—NH—(CH₂)₅—CH₃  15. OH O —(CH₂)₂—NHSO₂—(CH₂)₅—CH₃  16. OH O—(CH₂)₂—NHSO₂—(CH₂)₆—CH₃  17. OH O —(CH₂)₂—NHSO₂—(CH₂)₇—CH₃  18. OH O—(CH₂)₂—NHSO₂—(CH₂)₈—CH₃  19. OH O —(CH₂)₂—NHSO₂—(CH₂)₉—CH₃  20. OH O—(CH₂)₂—NHSO₂—(CH₂)₁₀—CH₃  21. OH O —(CH₂)₂—NHSO₂—(CH₂)₁₁—CH₃  22. OH O—(CH₂)₂—NHSO₂—(CH₂)₁₂—CH₃  23. OH O —(CH₂)₂—OSO₂—(CH₂)₅—CH₃  24. OH O—(CH₂)₂—OSO₂—(CH₂)₆—CH₃  25. OH O —(CH₂)₂—OSO₂—(CH₂)₇—CH₃  26. OH O—(CH₂)₂—OSO₂—(CH₂)₈—CH₃  27. OH O —(CH₂)₂—OSO₂—(CH₂)₉—CH₃  28. OH O—(CH₂)₂—OSO₂—(CH₂)₁₀—CH₃  29. OH O —(CH₂)₂—OSO₂—(CH₂)₁₁—CH₃  30. OH O—(CH₂)₂—OSO₂—(CH₂)₁₂—CH₃  31. OH O —(CH₂)₂—OSO₂—(CH₂)₁₃—CH₃  32. OH O—(CH₂)₂—OSO₂—(CH₂)₁₄—CH₃  33. OH O —(CH₂)₂—NH—(CH₂)₂—CH₃  34. OH O—(CH₂)₂—NH—(CH₂)₃—CH₃  35. OH O —(CH₂)₂—NH—(CH₂)₄—CH₃  36. OH O—(CH₂)₂—NH—(CH₂)₅—CH₃  37. OH O —(CH₂)₂—NH—(CH₂)₆—CH₃  38. OH O—(CH₂)₂—NH—(CH₂)₇—CH₃  39. OH O —(CH₂)₂—NH—(CH₂)₈—CH₃  40. OH O—(CH₂)₂—NH—(CH₂)₉—CH₃  41. OH O —(CH₂)₂—NH—(CH₂)₁₀—CH₃  42. OH O—(CH₂)₂—NH—(CH₂)₁₁—CH₃  43. OH O —(CH₂)₂—NH—(CH₂)₁₂—CH₃  44. OH O—(CH₂)₂—NH—(CH₂)₁₃—CH₃  45. OH O —(CH₂)₂—NH—(CH₂)₁₄—CH₃  46. OH O—(CH₂)₂—OC(O)—(CH₂)₅—CH₃  47. OH O —(CH₂)₂—OC(O)—(CH₂)₆—CH₃  48. OH O—(CH₂)₂—OC(O)—(CH₂)₇—CH₃  49. OH O —(CH₂)₂—OC(O)—(CH₂)₈—CH₃  50. OH O—(CH₂)₂—OC(O)—(CH₂)₉—CH₃  51. OH O —(CH₂)₂—OC(O)—(CH₂)₁₀—CH₃  52. OH O—(CH₂)₂—OC(O)—(CH₂)₁₁—CH₃  53. OH O —(CH₂)₂—OC(O)—(CH₂)₁₂—CH₃  54. OH O—(CH₂)₂—OC(O)—(CH₂)₁₃—CH₃  55. OH O —(CH₂)₂—C(O)O—(CH₂)₅—CH₃  56. OH O—(CH₂)₂—C(O)O—(CH₂)₆—CH₃  57. OH O —(CH₂)₂—C(O)O—(CH₂)₇—CH₃  58. OH O—(CH₂)₂—C(O)O—(CH₂)₈—CH₃  59. OH O —(CH₂)₂—C(O)O—(CH₂)₉—CH₃  60. OH O—(CH₂)₂—C(O)O—(CH₂)₁₀—CH₃  61. OH O —(CH₂)₂—C(O)O—(CH₂)₁₁—CH₃  62. OH O—(CH₂)₂—C(O)O—(CH₂)₁₂—CH₃  63. OH O —(CH₂)₂—NHSO₂—(CH₂)₅—CH₃  64. OH O—(CH₂)₂—NHSO₂—(CH₂)₆—CH₃  65. OH O —(CH₂)₂—NHSO₂—(CH₂)₇—CH₃  66. OH O—(CH₂)₂—NHSO₂—(CH₂)₈—CH₃  67. OH O —(CH₂)₂—NHSO₂—(CH₂)₉—CH₃  68. OH O—(CH₂)₂—NHSO₂—(CH₂)₁₀—CH₃  69. OH O —(CH₂)₂—NHSO₂—(CH₂)₁₁—CH₃  70. OH O—(CH₂)₂—NHSO₂—(CH₂)₁₂—CH₃  71. OH O —(CH₂)₂—NHC(O)—(CH₂)₅—CH₃  72. OH O—(CH₂)₂—NHC(O)—(CH₂)₆—CH₃  73. OH O —(CH₂)₂—NHC(O)—(CH₂)₇—CH₃  74. OH O—(CH₂)₂—NHC(O)—(CH₂)₈—CH₃  75. OH O —(CH₂)₂—NHC(O)—(CH₂)₉—CH₃  76. OH O—(CH₂)₂—NHC(O)—(CH₂)₁₀—CH₃  77. OH O —(CH₂)₂—NHC(O)—(CH₂)₁₁—CH₃  78. OHO —(CH₂)₂—NHC(O)—(CH₂)₁₂—CH₃  79. OH O

 80. OH O —(CH₂)₂—OC(O)—(CH₂)₆—CH₃  81. OH O —(CH₂)₂—OC(O)—(CH₂)₇—CH₃ 82. OH O —(CH₂)₂—OC(O)—(CH₂)₈—CH₃  83. OH O —(CH₂)₂—OC(O)—(CH₂)₉—CH₃ 84. OH O —(CH₂)₂—OC(O)—(CH₂)₁₀—CH₃  85. OH O —(CH₂)₂—OC(O)—(CH₂)₁₁—CH₃ 86. OH O —(CH₂)₂—OC(O)—(CH₂)₁₂—CH₃  87. OH O —(CH₂)₂—C(O)NH—(CH₂)₅—CH₃ 88. OH O —(CH₂)₂—C(O)NH—(CH₂)₆—CH₃  89. OH O —(CH₂)₂—C(O)NH—(CH₂)₇—CH₃ 90. OH O —(CH₂)₂—C(O)NH—(CH₂)₈—CH₃  91. OH O —(CH₂)₂—C(O)NH—(CH₂)₉—CH₃ 92. OH O —(CH₂)₂—C(O)NH—(CH₂)₁₀—CH₃  93. OH O—(CH₂)₂—C(O)NH—(CH₂)₁₁—CH₃  94. OH O —(CH₂)₂—C(O)NH—(CH₂)₁₂—CH₃  95. OHO —(CH₂)₂—S—(CH₂)₅—CH₃  96. OH O —(CH₂)₂—S—(CH₂)₆—CH₃  97. OH O—(CH₂)₂—S—(CH₂)₇—CH₃  98. OH O —(CH₂)₂—S—(CH₂)₈—CH₃  99. OH O—(CH₂)₂—S—(CH₂)₉—CH₃ 100. OH O —(CH₂)₂—S—(CH₂)₁₀—CH₃ 101. OH O—(CH₂)₂—S—(CH₂)₁₁—CH₃ 102. OH O —(CH₂)₂—S—(CH₂)₁₂—CH₃ 103. OH O—(CH₂)₃—NH—(CH₂)₅—CH₃ 104. OH O —(CH₂)₃—NH—(CH₂)₆—CH₃ 105. OH O—(CH₂)₃—NH—(CH₂)₇—CH₃ 106. OH O —(CH₂)₃—NH—(CH₂)₈—CH₃ 107. OH O—(CH₂)₃—NH—(CH₂)₉—CH₃ 108. OH O —(CH₂)₃—NH—(CH₂)₁₀—CH₃ 109. OH O—(CH₂)₃—NH—(CH₂)₁₁—CH₃ 110. OH O —(CH₂)₃—NH—(CH₂)₁₂—CH₃ 111. OH O—(CH₂)₄—NH—(CH₂)₅—CH₃ 112. OH O —(CH₂)₄—NH—(CH₂)₆—CH₃ 113. OH O—(CH₂)₄—NH—(CH₂)₇—CH₃ 114. OH O —(CH₂)₄—NH—(CH₂)₈—CH₃ 115. OH O—(CH₂)₄—NH—(CH₂)₉—CH₃ 116. OH O —(CH₂)₄—NH—(CH₂)₁₀—CH₃ 117. OH O—(CH₂)₄—NH—(CH₂)₁₁—CH₃ 118. OH O —(CH₂)₄—NH—(CH₂)₁₂—CH₃ 119. OH O—(CH₂)₅—NH—(CH₂)₅—CH₃ 120. OH O —(CH₂)₅—NH—(CH₂)₆—CH₃ 121. OH O—(CH₂)₅—NH—(CH₂)₇—CH₃ 122. OH O —(CH₂)₅—NH—(CH₂)₈—CH₃ 123. OH O—(CH₂)₅—NH—(CH₂)₉—CH₃ 124. OH O —(CH₂)₅—NH—(CH₂)₁₀—CH₃ 125. OH O—(CH₂)₅—NH—(CH₂)₁₁—CH₃ 126. OH O —(CH₂)₅—NH—(CH₂)₁₂—CH₃ 127. OH O—(CH₂)₂—N[(CH₂)₉CH₃]₂ 128. OH O —(CH₂)₅—NH—(CH₂)₅—CH(CH₃)₂ 129. OH O—(CH₂)₅—NH—(CH₂)₆—CH(CH₃)₂ 130. OH O —(CH₂)₅—NH—(CH₂)₇—CH(CH₃)₂ 131. OHO —(CH₂)₅—NH—(CH₂)₈—CH(CH₃)₂ 132. OH O —(CH₂)₅—NH—(CH₂)₉—CH(CH₃)₂ 133.OH O —(CH₂)₅—NH—(CH₂)₁₀—CH(CH₃)₂ 134. OH O —(CH₂)₂—NH—CH₂—Ph 135. OH O—(CH₂)₂—NH—(CH₂)₂—Ph 136. OH O —(CH₂)₂—NH—(CH₂)₃—Ph 137. OH O—(CH₂)₂—NH—(CH₂)₄—Ph 138. OH O —(CH₂)₂—NH—(CH₂)₅—Ph 139. OH O—(CH₂)₂—NH—(CH₂)₆—Ph 140. OH O —(CH₂)₂—NH—(CH₂)₇—Ph 141. OH O—(CH₂)₂—NH—(CH₂)₈—Ph 142. OH O —(CH₂)₂—NH—CH₂—4- [(CH₃)₂CHCH₂—]Ph 143.OH O —(CH₂)₂—NH—CH₂—4-(Ph—S—)Ph 144. OH O —(CH₂)₂—NH—CH₂—4-(4-CF₃—Ph)Ph145. OH O —(CH₂)₂—NH—CH₂—4-{4- [CH₃(CH₂)₄O—]—Ph}—Ph 146. OH O—(CH₂)₂—NH—CH₂—4-Cl—Ph 147. OH O —(CH₂)₂—NH—(CH₂)₂—4-Cl—Ph 148. OH O—(CH₂)₂—NH—(CH₂)₃—4-Cl—Ph 149. OH O —(CH₂)₂—NH—(CH₂)₄—4-Cl—Ph 150. OH O—(CH₂)₂—NH—(CH₂)₅—4-Cl—Ph 151. OH O —(CH₂)₂—NH—(CH₂)₆—4-Cl—Ph 152. OH O—(CH₂)₂—NH—(CH₂)₇—4-Cl—Ph 153. OH O —(CH₂)₂—NH—(CH₂)₈—4-Cl—Ph 154. OH O—(CH₂)₂—NH—CH₂—4-Ph—Ph 155. OH O —(CH₂)₂—NH—CH₂—4-(4-Cl—Ph)—Ph 156. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₂O—]Ph 157. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₃O—]Ph 158. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₄O—]Ph 159. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₅O—]Ph 160. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₆O—]Ph 161. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₇O—]Ph 162. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₈O—]Ph 163. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₂—]Ph 164. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₃—]Ph 165. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₄—]Ph 166. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₅—]Ph 167. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₆—]Ph 168. OH O —(CH₂)₂—NH—CH₂—3-[Ph—S—]Ph169. OH O —(CH₂)₂—NH—CH₂—4-[Ph—O—]Ph 170. OH O—(CH₂)₂—NH—CH₂—4-[CH₃CH₂Ph—O—]Ph 171. OH O —(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₂Ph—O—]Ph 172. OH O —(CH₂)₂—NH—CH₂— 4-[CH₃(CH₂)₃Ph—O—]Ph 173.OH O —(CH₂)₂—NH—CH₂— 4-[CH₃(CH₂)₄Ph—O—]Ph 174. OH O —(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₅Ph—O—]Ph 175. OH O —(CH₂)₂—NH—CH₂— 4-[CH₃(CH₂)₆Ph—O—]Ph 176.OH O —(CH₂)₂—NH—CH₂— 4-[CH₃(CH₂)₇Ph—O—]Ph 177. OH O —(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₈Ph—O—]Ph 178. OH O —(CH₂)₂—NH—CH₂— 4-[CH₃(CH₂)₉Ph—O—]Ph 179.OH O —(CH₂)₂—NH—CH₂—3-[Ph—S—]Ph 180. OH O —(CH₂)₂—NH—CH₂—4-[Ph—S—]Ph181. OH O —(CH₂)₂—NH—CH₂-cyclopropyl 182. OH O—(CH₂)₂—NH—(CH₂)₂-cyclopropyl 183. OH O —(CH₂)₂—NH—CH₂-cyclopentyl 184.OH O —(CH₂)₂—NH—(CH₂)₂-cyclopentyl 185. OH O —(CH₂)₂—NH—CH₂-cyclohexyl186. OH O —(CH₂)₂—NH—(CH₂)₂-cyclohexyl 187. OH O—(CH₂)₂—NH—(CH₂)₈—CH═CH₂ 188. OH O —(CH₂)₂—NH—(CH₂)₈—CH(OH)—CH₃ 189. OHO —(CH₂)₂—NH—(CH₂)₃CH═CH(CH₂)₄CH₃ (trans) 190. OH O—(CH₂)₂—NH—CH₂CH═C(CH₃)(CH₂)₂— CH═C(CH₃)₂ (trans, trans) 191. OH O—(CH₂)₂—NHC(O)—(CH₂)₆—CH(CH₃)CH₃ 192. OH O —(CH₂)₂—S—(CH₂)₈Ph 193. OH O—(CH₂)₂NH—CH₂—4-[(CH₃)₃CO]—Ph 194. OH O —(CH₂)₂—S—(CHO)₃CH≡CH(CH₂)₄CH₃(trans) 195. OH O —(CH₂)₂NH—CH₂—3,4-di-(CH₃CH₂O)—Ph 196. OH O—(CH₂)₂—S—CH₂CH₂(CF₂)₅CF₃ 197. OH O —(CH₂)₂NH—CH₂—4-[(CH₃)₂CH]—Ph 198.OH O —(CH₂)₂—S—CH₂—4-[(CH₃)₂CHCH₂—]Ph 199. OH O—(CH₂)₂—NH—CH₂—4-[CH₃(CH₂)₃C≡C]—Ph 200. OH O —(CH₂)₂—S—(CH₂)₁₁CH₃ 201.OH O —(CH₂)₂—NH—CH₂—4-[(CH₃)₂CHO]—Ph 202. OH O —(CH₂)₂—S—(CH₂)8CH₃ 203.OH O —(CH₂)₂—NH—CH₂—4-(Ph—≡C)—Ph 204. OH O—(CH₂)₂—S—CH₂3,4-di(PhCH₂O—)Ph 205. OH O —(CH₂)₂—NH—CH₂—4-[(CH₃)₃C]—Ph206. OH O —(CH₂)₃—S—(CH₂)₈Ph 207. OH O —(CH₂)₂—NH—CH₂—5-(PhC≡C)-thiophen-2-yl 208. OH O —(CH₂)₃—S—(CH₂)₈CH₃ 209. OH O—(CH₂)₂—NH—CH₂—4-(PhCH≡CH—)Ph (trans) 210. OH O —(CH₂)₃—S—(CH₂)₉CH₃ 211.OH O —(CH₂)₂—NH—CH₂—(CH≡CH)₄—CH₃ (trans, trans, trans, trans) 212. OH O—(CH₂)₃—S—(CH₂)₆Ph 213. OH O —(CH₂)₂—N(C(O)Ph)—(CH₂)₉CH₃ 214. OH O—(CH₂)₄—S—(CH₂)₇CH₃ 215. OH O —(CH₂)₂—NH—CH₂—4-[4-(CH₃)₃C-thiozol-2-yl]—Ph 216. OH O —(CH₂)₂—S—(CH₂)₆Ph 217. OH O—(CH₂)₂—N[(CH₂)₉CH₃]— C(O)CHrS-4-pyridyl 218. OH O —(CH₂)₂—S—(CH₂)₁₀Ph219. OH O —(CH₂)₂—N[(CH₂)₉CH₃]— C(O)-2-[PhCH(CH₃)NHC(O)—]Ph (R isomer)220. OH O —(CH₂)₃—S—CH₂— 4-[(CH₃)₂CHCH₂—]Ph 221. OH O—(CH₂)₂—N[(CH₂)₉CH₃]— C(O)-(1-PhCH₂OC(O)—2- oxoimidazolidin-5-yl) (Sisomer) 222. OH O —(CH₂)₂—S—(CH₂)₃CH≡CH(CH₂)₄CH₃ (trans) 223. OH O—(CH₂)₂—N[(CH₂)₉CH₃]— C(O)-1-HO-cyclopropyl 224. OH O—(CH₂)₂—S—CH₂-4-[3,4- di-Cl—PhCH₂O—]Ph 225. OH O —(CH₂)₂—N(C(O)CH₂—naphth-2-yl)—(CH₂)₉CH 226. OH O —(CH₂)₃—S—CH₂-4-[3,4- di-Cl—PhCH₂O—]Ph227. OH O —(CH₂)₂—N[C(O)(CH₂)₉CH₂OH]—(CH₂)₉CH₃ 228. OH O—(CH₂)₂—SO—4-(4-Cl—Ph)—Ph 229. OH O —CH₂CH₂—N[C(O)CH₂(OCH₂CH₂)₂OCH₃]—(CH₂)₉CH₃ 230. OH O —(CH₂)₃—SO—4-(4-Cl—Ph)—Ph 231. OH O—(CH₂)₂—N[C(O)CH₂CH(Ph)₂]— (CH₂)₉CH₃ 232. OH O —(CH₂)₂—S—(CH₂)₁₀CH₃ 233.OH O —(CH₂)₂—N(C(O)CH₂—3-HO—Ph)— (CH₂)₉CH₃ 234. OH O—(CH₂)₃—S—(CH₂)₁₀CH₃ 235. OH O —(CH₂)₂—N(C(O)CH₂—NHC(O)—3-CH₃—Ph)—(CH₂)₉CH₃ 236. OH O —(CH₂)₃—S—CH₂-4-(CH₃(CH₂)₄O—]Ph 237. OH O—(CH₂)₂—N(C(O)CH₂CH₂—O—Ph)— (CH₂)₉CH₃ 238. OH O —(CH₂)₃—S—CH₂CH≡CH—CH≡CH(CH₂)₄CH₃(trans, trans) 239. OH O —(CH₂)₂—N(C(O)CH₂CH₂—3-pyridyl)—(CH₂)₉CH₃ 240. OH O —(CH₂)₂—S—CHr4-[4-Cl—PhCH₂O—]Ph 241. OH O—(CH₂)₂—N(C(O)(CH₂)₃— 4-CH₃O—Ph)—(CH₂)₉CH₃ 242. OH O—(CH₂)₃—S—CH₂4-[4-Cl—PhCH₂O—]Ph 243. OH O —(CH₂)₂—N(C(O)-indol-2-yl)-(CH₂)₉CH₃ 244. OH O —(CH₂)₃—S—CH₂-4-(4-CF₃—Ph—)Ph 245. OH O—(CH₂)₂—N{C(O)-1- [CH₃COC(O)—]-pyrrolidin-2-yl}-(CH₂)₉CH₃ 246. OH O—(CH₂)₃—S—CH₂-4- (4-F—PhSO₂NH—)Ph 247. OH O—(CH₂)₂—N(C(O)CH₂—NHC(O)—CH═CH- furan-2-yl)-(CH₂)₉CH₃ (trans) 248. OH O—(CH₂)₃—S—(CH₂)₈CH₃ 249. OH O —(CH₂)₂—N[C(O)-1-CH₃CHr 7-CH₃-4-oxo-1,4-dihydro[1,8]naphthyridin-3-yl]-(CH₂)₉CH₃ 250. OH O—(CH₂)₃—S(O)—(CH₂)₆Ph 251. OH O —(CH₂)₂—N(C(O)-1,3-benzodioxol-5-yl)-(CH₂)₉CH₃ 252. OH O —(CH₂)₂—S(O)—(CH₂)₈Ph 253. OH O—(CH₂)₂—N(C(O)CH₂-4-oxo-2- thiooxothiazolidin-₃-yl)-(CH₂)₉CH₃ 254. OH O—(CH₂)₂—S—(CH₂)₃-4-Cl—Ph 255. OH O—(CH₂)₂—N(C(O)-3,4,5-tri-HO-cyclohex-1-en- 1-yl)-(CH₂)₉CH₃ (R,S,Risomer) 256. OH O —(CH₂)₂—S—(CH₂)c4-Cl—Ph 257. OH O—(CH₂)₂—N(C(O)CH₂CH₂C(O)NH₂)— (CH₂)₉CH₃ 258. OH O —(CH₂)₂—SO₂—(CH₂)₉CH₃259. OH O —(CH₂)₂—N(C(O)(CH₂)5—CH₃-2,4-dioxo-3,4-dihydropyrimidin-1-yl)-(CH₂)₉CH₃ 260. OH O—(CH₂)₂—NHC(O)—CH₂CH(CH₂CH₂Ph)—{3-[4-(9H-flouren-9-ylCH₂OC(O)NH(CH₂)₄—]-1,4-dioxohexahydro-1,2-α-pyrazin-2-yl} (S,S,S isomer) 261. OH O—(CH₂)₂—N(C(O)CH≡CH—imidazol-4-yl)- (CH₂)₉CH₃ (trans) 262. OH O—(CH₂)₂—NHSO₂—4-(2-Cl—Ph)—Ph 263. OH O —(CH₂)₂—N[C(O)CH(CH₂CH₂C(O)NH₂)—NHC(O)O—CH₂Ph]—(CH₂)₉CH₃(S isomer) 264. OH O—(CH₂)₂—NHSO₂—4-[4-(CH₃)₃C—Ph]—Ph 265. OH O —(CH₂)₂—N[C(O)CH(CH₂OH)—NHC(O)O—CH₂Ph]—(CH₂)₉CH₃(S isomer) 266. OH O—(CH₂)₂—NHSO₂—4-[4-(Ph)—Ph—]Ph 267. OH O —(CH₂)₂—N[C(O)CH[CH(OH)CH₃]NH—C(O)O—CH₂Ph]—(CH₂)₉CH₃(S isomer) 268. OH O —(CH₂)₂—NH—4-(4-CF₃—Ph)—Ph269. OH O —(CH₂)₂—N(C(O)CH₂NHSO₂-4- CH₃—Ph)—(CH₂)₉CH₃(S isomer) 270. OHO —(CH₂)₂—N(C(O)CH(NH₂)CHr₃— HO—Ph)—(CH₂)₉CH₃ 271. OH O—(CH₂)₂—N(C(O)(CH₂)₃—NH₂)—(CH₂)₉CH₃ 272. OH O —(CH₂)₂—N(C(O)CH(NH₂)CH₃)—(CH₂)₉CH₃(R isomer) 273. OH O —(CH₂)₂—N(C(O)—pyrrolidin-2-yl)- (CH₂)₉CH₃274. OH O —(CH₂)₂—N[C(O)CH(CH₂OH)NHC(O)— CH₃]—(CH₂)₉CH₃(S isomer) 275.OH O —(CH₂)₂—N(C(O)—pyrrolidin-2-yl)- (CH₂)₉CH₃(R isomer) 276. OH O—(CH₂)₂—N[C(O)CH(NHC(O)CH₃— (CH₂)₃—NHC(NH)NH₂]—(CH₂)₉CH₃(S isomer) 277.OH O —(CH₂)₂—N(C(O)CH(NH₂)(CH₂)4- NH₂)—(CH₂)₉CH₃(S isomer) 278. OH O—(CH₂)₂—N(C(O)CH₂NHC(O)CH₃)— (CH₂)₉CH₃ 279. OH O—(CH₂)₂—N(C(O)-5-oxopyrrolidin-2-yl)- (CH₂)₉CH₃(R isomer) 280. OH O—(CH₂)₂—N(C(O)CH(CH₃)OC(O)CH— (NH₂)(CH₃)—(CH₂)₉CH₃(R,R isomer) 281.—N(CH₂)₂ O

282. —N(CH₂)₂ NH

283. —N(CH₂)₂ S

284. —N(CH₂)₂ H₂

285.

O

286.

NH

287.

S

288.

H₂

289. —N⁺(CH₂)₃ O

290. —N⁺(CH₂)₃ NH

291. —N⁺(CH₂)₃ S

292. —N⁺(CH₂)₃ H₂

293. OH O

294. OH O —(CH₂)₂—OC(O)—(CH₂)₅—CH₃ Ph- phenyl

In one embodiment, the compound is a prodrug of Formula (I) or Formula(II), for example an alkyl ester prodrug. The alkyl group in oneembodiment is a straight chain C₁-C₂₀ alkyl or a branched C₁-C₂₀ alkyl.The alkyl ester attachment can be at any oxygen in the molecule,determined by the user of the method.

In one embodiment of the invention, a compound of Formula (I), Formula(II), or a pharmaceutically acceptable salt of Formula (I) or Formula(II), is delivered to a patient in need thereof, wherein, X is O, R¹ isa C₁-C₁₈ linear alkyl, R² is OH, and R³ and R⁴ are H.

R¹ in a further embodiment is a C₇-C₁₇ linear alkyl; C₇-C₁₀ or C₆-C₁₀linear alkyl.

In yet another embodiment, a compound of Formula (I), Formula (II) aprodrug thereof, or a pharmaceutically acceptable salt thereof, isdelivered to a patient in need thereof, wherein, X is O, R¹ isR⁵—Y—R⁶—(Z)_(n), R² is OH, and R³ and R⁴ are H.

In a further embodiment, R⁵ is —(CH₂)₂—, R⁶ is —(CH₂)₁₀—, Y is NR, Z ishydrogen and n is 1. In a further embodiment, R⁸ is hydrogen and X is O.In even a further embodiment, the administering is intravenous or viathe pulmonary route.

In one embodiment of the invention, a compound of Formula (I), Formula(II) or a pharmaceutically acceptable salt thereof, is delivered to apatient in need of bacterial infection treatment, where R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃, X is O, R² is —NH—(CH₂)_(q)—R⁷, and R³ and R⁴ areH. In a further embodiment, q is 2 or 3 and R¹ is —N(CH₂)₂.

In one embodiment of the invention, a compound of Formula (I), Formula(II) or a pharmaceutically acceptable salt thereof, is delivered to apatient in need of bacterial infection treatment, where R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃, X is O, R² is OH, R³ is

and R⁴ is H.

In one embodiment, a compound of Formula (I), Formula (II) or apharmaceutically acceptable salt thereof, is delivered to a patient inneed of bacterial infection treatment, where R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃, X is O, R² is OH, and R³ is H and R⁴ isCH₂—NH—CH₂—PO₃H₂.

In yet another embodiment, a compound of Formula (I) or Formula (II) isprovided, wherein one or more hydrogen atoms is replaced with adeuterium atom. In a further embodiment, R²—Y—R³—(Z) is—(CH₂)₂—NH—(CH₂)₉—CH₃.

In one embodiment of the treatment methods provided herein, the compoundof Formula (I), Formula (II), or a pharmaceutically acceptable salt ofFormula (I) or Formula (II), is defined as follows: R¹ is(CH₂)_(n1)—Y—(CH₂)_(n2)—CH₃, R² is OH, R³ and R⁴ are H, n2 is an integerselected from 1 to 6 and n3 is an integer from 1 to 15. In a furtherembodiment, X is O. In even a further embodiment, the administering isintravenous or via the pulmonary route.

In one embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isdelivered to a patient in need of bacterial infection treatment, whereR¹ is (CH₂)—Y—(CH₂)_(n2)—CH₃, R² is OH, R³ and R⁴ are H and X is O. In afurther embodiment, Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO₂—.In a further embodiment, Y is —NH—.

In one embodiment, a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is delivered to a patient in need of bacterialinfection treatment, where R¹ is (CH₂)₂—Y—(CH₂)_(n2)—CH₃, R² is OH, R³and R⁴ are H and X is O. In a further embodiment, Y is oxygen, sulfur,—S—S—, —NH—, —S(O)— or —SO₂—. In a further embodiment, Y is —NH—.

In one embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isdelivered to a patient in need of bacterial infection treatment, whereR¹ is (CH₂)₃—Y—(CH₂)₂—CH₃, R² is OH, R³ and R⁴ are H and X is O. In afurther embodiment, Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO₂—.In a further embodiment, Y is —NH—.

In one embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isdelivered to a patient in need of bacterial infection treatment, whereR¹ is (CH₂)₁₋₃—Y—(CH₂)₈—CH₃, R² is OH, R³ and R⁴ are H and X is O. In afurther embodiment, Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO₂—.In a further embodiment, Y is —NH—.

In one embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isdelivered to a patient in need of bacterial infection treatment, whereR¹ is (CH₂)₁₋₃—Y—(CH₂)₉—CH₃, R² is OH, R³ and R⁴ are H and X is O. In afurther embodiment, Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO₂—.In a further embodiment, Y is —NH—.

In one embodiment, a compound of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II), isdelivered to a patient in need of bacterial infection treatment, whereR¹ is (CH₂)₂—Y—(CH₂)₁—CH₃, R² is OH, R³ and R⁴ are H and X is O. In afurther embodiment, Y is oxygen, sulfur, —S—S—, —NH—, —S(O)— or —SO₂—.In a further embodiment, Y is —NH—.

Compositions provided herein can be in the form of a solution,suspension or dry powder. Compositions can be administered by techniquesknown in the art, including, but not limited to intramuscular,intravenous, intratracheal, intranasal, intraocular, intraperitoneal,subcutaneous, and transdermal routes. In addition, as discussedthroughout, the compositions can also be administered via the pulmonaryroute, e.g., via inhalation with a nebulizer or a dry powder inhaler.

In one embodiment, the composition provided herein comprises a pluralityof nanoparticles of the antibiotic of Formula (I), Formula (II), or apharmaceutically acceptable salt of Formula (I) or Formula (II) inassociation with a polymer. The mean diameter of the plurality ofnanoparticles, in one embodiment, is from about 50 nm to about 900 nm,for example from about 10 nm to about 800 nm, from about 100 nm to about700 nm, from about 100 nm to about 600 nm or from about 100 nm to about500 nm.

In one embodiment, the plurality of nanoparticles comprise abiodegradable polymer and the antibiotic of Formula (I), Formula (II),or a pharmaceutically acceptable salt of Formula (I) or Formula (II). Ina further embodiment, the biodegradable polymer is poly(D,L-lactide),poly(lactic acid) (PLA), poly(D,L-glycolide) (PLG),poly(lactide-co-glycolide) (PLGA), poly-(cyanoacrylate) (PCA), or acombination thereof.

In even a further embodiment, the biodegradable polymer ispoly(lactic-co-glycolitic acid) (PLGA).

Nanoparticle compositions can be prepared according to methods known tothose of ordinary skill in the art. For example, coacervation, solventevaporation, emulsification, in situ polymerization, or a combinationthereof can be employed (see, e.g., Soppimath et al. (2001). Journal ofControlled Release 70, pp. 1-20, incorporated by reference herein in itsentirety for all purposes).

The amount of polymer in the composition can be adjusted, for example,to adjust the release profile of the compound of Formula from thecomposition.

In one embodiment, a dry powder composition disclosed in one of U.S.Pat. Nos. 5,874,064, 5,855,913 and/or U.S. Patent ApplicationPublication No. 2008/0160092 is used to formulate one of theglycopeptides of Formula (I), Formula (II), or a pharmaceuticallyacceptable salt of Formula (I) or Formula (II). The disclosures of U.S.Pat. Nos. 5,874,064, 5,855,913 and U.S. Patent Application PublicationNo. 2008/0160092 are each incorporated by reference herein in theirentireties for all purposes.

In one embodiment, the composition delivered via the methods providedherein are spray dried, hollow and porous particulate compositions. Forexample, the hollow and porous particulate compositions as disclosed inWO 1999/16419, hereby incorporated in its entirety by reference for allpurposes, can be employed. Such particulate compositions compriseparticles having a relatively thin porous wall defining a large internalvoid, although, other void containing or perforated structures arecontemplated as well.

Compositions delivered via the methods provided herein, in oneembodiment, yield powders with bulk densities less than 0.5 g/cm³ or 0.3g/cm³, for example, less 0.1 g/cm3, or less than 0.05 g/cm³. Byproviding particles with very low bulk density, the minimum powder massthat can be filled into a unit dose container is reduced, whicheliminates the need for carrier particles. Moreover, the elimination ofcarrier particles, without wishing to be bound by theory, can minimizethroat deposition and any “gag” effect, since the large lactoseparticles can impact the throat and upper airways due to their size.

In some embodiments, the particulate compositions delivered via themethods provided herein comprise a structural matrix that exhibits,defines or comprises voids, pores, defects, hollows, spaces,interstitial spaces, apertures, perforations or holes. The particulatecompositions in one embodiment, are provided in a “dry” state. That is,the particulate composition possesses a moisture content that allows thepowder to remain chemically and physically stable during storage atambient temperature and easily dispersible. As such, the moisturecontent of the microparticles is typically less than 6% by weight, andfor example, less 3% by weight. In some embodiments, the moisturecontent is as low as 1% by weight. The moisture content is, at least inpart, dictated by the formulation and is controlled by the processconditions employed, e.g., inlet temperature, feed concentration, pumprate, and blowing agent type, concentration and post drying.

Reduction in bound water can lead to improvements in the dispersibilityand flowability of phospholipid based powders, leading to the potentialfor highly efficient delivery of powdered lung surfactants orparticulate composition comprising active agent dispersed in thephospholipid.

The composition administered via the methods provided herein, in oneembodiment, is a particulate composition comprising a compound ofFormula (I) or Formula (II), a phospholipid and a polyvalent cation. Inparticular, the compositions of the present invention can employpolyvalent cations in phospholipid-containing, dispersible particulatecompositions for pulmonary administration to the respiratory tract forlocal or systemic therapy via aerosolization.

Without wishing to be bound by theory, it is thought that the use of apolyvalent cation in the form of a hygroscopic salt such as calciumchloride stabilizes a dry powder prone to moisture inducedstabilization. Without wishing to be bound by theory, it is thought thatsuch cations intercalate the phospholipid membrane, thereby interactingdirectly with the negatively charged portion of the zwitterionicheadgroup. The result of this interaction is increased dehydration ofthe headgroup area and condensation of the acyl-chain packing, all ofwhich leads to increased thermodynamic stability of the phospholipids.Other benefits of such dry powder compositions are provided in U.S. Pat.No. 7,442,388, the disclosure of which is incorporated herein in itsentirety for all purposes.

The polyvalent cation for use in the present invention in oneembodiment, is a divalent cation. In a further embodiment, the divalentcation is calcium, magnesium, zinc or iron. The polyvalent cation ispresent in one embodiment, to increase the Tm of the phospholipid suchthat the particulate composition exhibits a Tm which is greater than itsstorage temperature Ts by at least 20° C. The molar ratio of polyvalentcation to phospholipid in one embodiment, is 0.05, e.g., from about 0.05to about 2.0, or from about 0.25 to about 1.0. In one embodiment, themolar ratio of polyvalent cation to phospholipid is about 0.50. In oneembodiment, the polyvalent cation is calcium and is provided as calciumchloride.

According to one embodiment, the phospholipid is a saturatedphospholipid. In a further embodiment, the saturated phospholipid is asaturated phosphatidylcholine. Acyl chain lengths that can be employedrange from about C₁₆ to C₂₂. For example, in one embodiment an acylchain length of 16:0 or 18:0 (i.e., palmitoyl and stearoyl) is employed.In one phospholipid embodiment, a natural or synthetic lung surfactantis provided as the phospholipid component. In this embodiment, thephospholipid can make up to 90 to 99.9% w/w of the lung surfactant.Suitable phospholipids according to this aspect of the invention includenatural or synthetic lung surfactants such as those commerciallyavailable under the trademarks ExoSurf, InfaSurf® (Ony, Inc.), Survanta,CuroSurf, and ALEC.

The Tm of the phospholipid-glycopeptide particles, in one embodiment, ismanipulated by varying the amount of polyvalent cations in thecomposition.

Phospholipids from both natural and synthetic sources are compatiblewith the compositions administered by the methods provided herein, andmay be used in varying concentrations to form the structural matrix.Generally compatible phospholipids comprise those that have a gel toliquid crystal phase transition greater than about 40° C. Theincorporated phospholipids in one embodiment, are relatively long chain(i.e., C₁₆-C₂₂) saturated lipids and in a further embodiment, comprisesaturated phospholipids. In even a further embodiment, the saturatedphospholipid is a saturated phosphatidylcholine. In even a furtherembodiment, the saturated phosphatidylcholine has an acyl chain lengthsof 16:0 or 18:0 (palmitoyl or stearoyl). Exemplary phospholipids usefulin the disclosed stabilized preparations comprise, phosphoglyceridessuch as dipalmitoylphosphatidylcholine (DPPC),disteroylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholinedibehenoylphosphatidylcholine, diphosphatidyl glycerol, short-chainphosphatidylcholines, long-chain saturated phosphatidylethanolamines,long-chain saturated phosphatidylserines, long-chain saturatedphosphatidylglycerols, long-chain saturated phosphatidylinositols.

In addition to the phospholipid, a co-surfactant or combinations ofsurfactants, including the use of one or more in the liquid phase andone or more associated with the particulate compositions can be used inthe compositions delivered via the methods provided herein. By“associated with or comprise” it is meant that the particulatecompositions may incorporate, adsorb, absorb, be coated with or beformed by the surfactant. Surfactants include fluorinated andnonfluorinated compounds and can include saturated and unsaturatedlipids, nonionic detergents, nonionic block copolymers, ionicsurfactants and combinations thereof. In one embodiment comprisingstabilized dispersions, nonfluorinated surfactants are relativelyinsoluble in the suspension medium.

Compatible nonionic detergents suitable as co-surfactants in thecompositions provided herein include sorbitan esters including sorbitantrioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate,sorbitan monolaurate, polyoxyethylene (20) (Brij® S20), sorbitanmonolaurate, and polyoxyethylene (20) sorbitan monooleate, oleylpolyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, laurylpolyoxyethylene (4) ether, glycerol esters, and sucrose esters. Blockcopolymers include diblock and triblock copolymers of polyoxyethyleneand polyoxypropylene, including poloxamer 188 (Pluronic® F-68),poloxamer 407 (Pluronic® F-127), and poloxamer 338. Ionic surfactantssuch as sodium sulfosuccinate, and fatty acid soaps may also beutilized.

The phospholipid-glycopeptide particulate compositions can includeadditional lipids such as a glycolipid, ganglioside GM1, sphingomyelin,phosphatidic acid, cardiolipin; a lipid bearing a polymer chain such aspolyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; alipid bearing sulfonated mono-, di-, and polysaccharides; a fatty acidsuch as palmitic acid, stearic acid, and/or oleic acid; cholesterol,cholesterol esters, and cholesterol hemisuccinate.

In addition to the phospholipid and polyvalent cation, the particulatecomposition delivered via the methods provided herein can also include abiocompatible, and in some embodiments, biodegradable polymer,copolymer, or blend or other combination thereof. The polymer in oneembodiment is a polylactide, polylactide-glycolide, cyclodextrin,polyacrylate, methylcellulose, carboxymethylcellulose, polyvinylalcohol, polyanhydride, polylactam, polyvinyl pyrrolidone,polysaccharide (e.g., dextran, starch, chitin, chitosan), hyaluronicacid, protein (e.g., albumin, collagen, gelatin, etc.).

Besides the aforementioned polymer materials and surfactants, otherexcipients can be added to a particulate composition, for example, toimprove particle rigidity, production yield, emitted dose anddeposition, shelf-life and/or patient acceptance. Such optionalexcipients include, but are not limited to: coloring agents, tastemasking agents, buffers, hygroscopic agents, antioxidants, and chemicalstabilizers. Other excipients may include, but are not limited to,carbohydrates including monosaccharides, disaccharides andpolysaccharides. For example, monosaccharides such as dextrose(anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol,sorbose and the like; disaccharides such as lactose, maltose, sucrose,trehalose, and the like; trisaccharides such as raffinose and the like;and other carbohydrates such as starches (hydroxyethylstarch),cyclodextrins and maltodextrins. Mixtures of carbohydrates and aminoacids are further held to be within the scope of the present invention.The inclusion of both inorganic (e.g., sodium chloride), organic acidsand their salts (e.g., carboxylic acids and their salts such as sodiumcitrate, sodium ascorbate, magnesium gluconate, sodium gluconate,tromethamine hydrochloride, etc.) and buffers can also be undertaken.Salts and/or organic solids such as ammonium carbonate, ammoniumacetate, ammonium chloride or camphor can also be employed.

According to one embodiment, the particulate compositions may be used inthe form of dry powders or in the form of stabilized dispersionscomprising a non-aqueous phase. The dispersions or powders of thepresent invention may be used in conjunction with metered dose inhalers(MDIs), dry powder inhalers (DPIs), atomizers, or nebulizers to providefor pulmonary delivery.

While several procedures are generally compatible with making certaindry powder compositions described herein, spray drying is a particularlyuseful method. As is well known, spray drying is a one-step process thatconverts a liquid feed to a dried particulate form. With respect topharmaceutical applications, it will be appreciated that spray dryinghas been used to provide powdered material for various administrativeroutes including inhalation. See, for example, M. Sacchetti and M. M.Van Oort in: Inhalation Aerosols: Physical and Biological Basis forTherapy, A. J. Hickey, ed. Marcel Dekkar, New York, 1996, which isincorporated herein by reference in its entirety for all purposes. Ingeneral, spray drying consists of bringing together a highly dispersedliquid, and a sufficient volume of hot air to produce evaporation anddrying of the liquid droplets. The preparation to be spray dried or feed(or feed stock) can be any solution, suspension, slurry, colloidaldispersion, or paste that may be atomized using the selected spraydrying apparatus. In one embodiment, the feed stock comprises acolloidal system such as an emulsion, reverse emulsion, microemulsion,multiple emulsion, particulate dispersion, or slurry. Typically, thefeed is sprayed into a current of warm filtered air that evaporates thesolvent and conveys the dried product to a collector. The spent air isthen exhausted with the solvent.

It will further be appreciated that spray dryers, and specifically theiratomizers, may be modified or customized for specialized applications,e.g., the simultaneous spraying of two solutions using a double nozzletechnique. More specifically, a water-in-oil emulsion can be atomizedfrom one nozzle and a solution containing an anti-adherent such asmannitol can be co-atomized from a second nozzle. In one embodiment, itmay be desirable to push the feed solution though a custom designednozzle using a high pressure liquid chromatography (HPLC) pump. Examplesof spray drying methods and systems suitable for making the dry powdersof the present invention are disclosed in U.S. Pat. Nos. 6,077,543,6,051,256, 6,001,336, 5,985,248, and 5,976,574, each of which isincorporated in their entirety by reference for all purposes.

While the resulting spray-dried powdered particles typically areapproximately spherical in shape, nearly uniform in size and frequentlyare hollow, there may be some degree of irregularity in shape dependingupon the incorporated glycopeptide of Formula (I) or Formula (II) andthe spray drying conditions. In one embodiment, an inflating agent (orblowing agent) is used in the spray-dried powder production, e.g., asdisclosed in WO 99/16419, incorporated by reference herein in itsentirety for all purposes. Additionally, an emulsion can be includedwith the inflating agent as the disperse or continuous phase. Theinflating agent can be dispersed with a surfactant solution, using, forinstance, a commercially available microfluidizer at a pressure of about5000 to 15,000 PSI. This process forms an emulsion, and in someembodiments, an emulsion stabilized by an incorporated surfactant, andcan comprise submicron droplets of water immiscible blowing agentdispersed in an aqueous continuous phase. The blowing agent in oneembodiment, is a fluorinated compound (e.g., perfluorohexane,perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin,perfluorobutyl ethane) which vaporizes during the spray-drying process,leaving behind generally hollow, porous aerodynamically lightmicrospheres. Other suitable liquid blowing agents includenonfluorinated oils, chloroform, Freons, ethyl acetate, alcohols andhydrocarbons. Nitrogen and carbon dioxide gases are also contemplated asa suitable blowing agent. Perfluorooctyl ethane is the blowing agent, inone embodiment.

Whatever components are selected, the first step in particulateproduction in one embodiment, comprises feed stock preparation. Theselected glycopeptide is dissolved in a solvent, for example water,dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile,ethanol, methanol, or combinations thereof, to produce a concentratedsolution. The polyvalent cation may be added to the glycopeptidesolution or may be added to the phospholipid emulsion as discussedbelow. The glycopeptide may also be dispersed directly in the emulsion,particularly in the case of water insoluble agents. Alternatively, theglycopeptide is incorporated in the form of a solid particulatedispersion. The concentration of the glycopeptide used is dependent onthe amount of glycopeptide required in the final powder and theperformance of the delivery device employed (e.g., the fine particledose for a MDI or DPI). As needed, cosurfactants such as poloxamer 188or span 80 may be dispersed into this annex solution. Additionally,excipients such as sugars and starches can also be added.

In one embodiment, a polyvalent cation-containing oil-in-water emulsionis then formed in a separate vessel. The oil employed in one embodiment,is a fluorocarbon (e.g., perfluorooctyl bromide, perfluorooctyl ethane,perfluorodecalin) which is emulsified with a phospholipid. For example,polyvalent cation and phospholipid may be homogenized in hot distilledwater (e.g., 60° C.) using a suitable high shear mechanical mixer (e.g.,Ultra-Turrax model T-25 mixer) at 8000 rpm for 2 to 5 minutes. In oneembodiment, 5 to 25 g of fluorocarbon is added dropwise to the dispersedsurfactant solution while mixing. The resulting polyvalentcation-containing perfluorocarbon in water emulsion is then processedusing a high pressure homogenizer to reduce the particle size. In oneembodiment, the emulsion is processed at 12,000 to 18,000 PSI, 5discrete passes and kept at 50 to 80° C.

The glycopeptide solution (or suspension) and perfluorocarbon emulsionare then combined and fed into the spray dryer. In one embodiment, thetwo preparations are miscible. While the glycopeptide is solubilizedseparately for the purposes of the instant discussion it will beappreciated that, in other embodiments, the glycopeptide may besolubilized (or dispersed) directly in the emulsion. In such cases, theglycopeptide emulsion is simply spray dried without combining a separateglycopeptide preparation.

Operating conditions such as inlet and outlet temperature, feed rate,atomization pressure, flow rate of the drying air, and nozzleconfiguration can be adjusted in accordance with the manufacturer'sguidelines in order to produce the desired particle size, and productionyield of the resulting dry particles. The selection of appropriateapparatus and processing conditions are well within the purview of askilled artisan. In one embodiment, the particulate compositioncomprises hollow, porous spray dried micro- or nano-particles.

Along with spray drying, particulate compositions useful in the presentinvention may be formed by lyophilization. Those skilled in the art willappreciate that lyophilization is a freeze-drying process in which wateris sublimed from the composition after it is frozen. Methods forproviding lyophilized particulates are known to those of skill in theart. The lyophilized cake containing a fine foam-like structure can bemicronized using techniques known in the art.

Besides the aforementioned techniques, the glycopeptide particulatecompositions or glycopeptide particles provided herein may be formedusing a method where a feed solution (either emulsion or aqueous)containing wall forming agents is rapidly added to a reservoir of heatedoil (e.g., perflubron or other high boiling FCs) under reduced pressure.The water and volatile solvents of the feed solution rapidly boils andare evaporated. In one embodiment, the wall forming agents are insolublein the heated oil. The resulting particles can then separated from theheated oil using a filtering technique and then dried under vacuum.

In another embodiment, the particulate compositions of the presentinvention may also be formed using a double emulsion method. In thedouble emulsion method, the medicament is first dispersed in a polymerdissolved in an organic solvent (e.g., methylene chloride, ethylacetate) by sonication or homogenization. This primary emulsion is thenstabilized by forming a multiple emulsion in a continuous aqueous phasecontaining an emulsifier such as polyvinylalcohol. Evaporation orextraction using conventional techniques and apparatus then removes theorganic solvent. The resulting particles are washed, filtered and driedprior to combining them with an appropriate suspension medium.

In order to maximize dispersibility, dispersion stability and optimizedistribution upon administration, the mean geometric particle size ofthe particulate compositions in one embodiment, is from about 0.5-50 μm,for example from about 0.5 μm to about 10 μm or from about 0.5 to about5 μm. In one embodiment, the mean geometric particle size (or diameter)of the particulate compositions is less than 20 μm or less than 10 μm.In a further embodiment, the mean geometric diameter is ≤about 7 μm or≤5 μm. In even a further embodiment, the mass geometric diameter is≤about 2.5 μm. In one embodiment, the particulate composition comprisesa powder of dry, hollow, porous spherical shells of from about 0.1 toabout 10 μm, e.g., from about 0.5 to about 5 μm in diameter, with shellthicknesses of approximately 0.1 μm to about 0.5 μm.

In addition to the glycopeptides of Formula (I), Formula (II) or apharmaceutically acceptable salt thereof, one or more additionalantiinfectives can be included in the composition administered to thepatient in need thereof, either in the same composition, or a differentcomposition. Additional antiinfectives include an additionalglycopeptide, for example, one of the glycopeptides described herein.Other additional antiinfectives include but are not limited toaminoglycosides (e.g., dibekacin, K-4619, sisomicin, amikacin,dactimicin, isepamicin, rhodestreptomycin, apramycin, etimicin, KA-5685,sorbistin, arbekacin, framycetin, kanamycin, spectinomycin, astromicin,gentamicin, neomycin, sporaricin, bekanamycin, H107, netilmicin,streptomycin, boholmycin, hygromycin, paromomycin, tobramycin,brulamycin, hygromycin B, plazomicin, verdamicin, capreomycin,inosamycin, ribostamycin, vertilmicin), tetracyclines (e.g.,chlortetracycline, oxytetracycline, methacycline, doxycycline,minocycline), sulfonamides (e.g., sulfanilamide, sulfadiazine,sulfamethaoxazole, sulfisoxazole, sulfacetamide), paraaminobenzoic acid,diaminopyrimidines (e.g., trimethoprim), quinolones (e.g., nalidixicacid, cinoxacin, ciprofloxacin and norfloxacin), penicillins (e.g.,penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin,carbenicillin, carbenicillin indanyl, ticarcillin, azlocillin,mezlocillin, piperacillin), penicillinase resistant penicillin (e.g.,methicillin, oxacillin, cloxacillin, dicloxacillin, nafcillin), firstgeneration cephalosporins (e.g., cefadroxil, cephalexin, cephradine,cephalothin, cephapirin, cefazolin), second generation cephalosporins(e.g., cefaclor, cefamandole, cefonicid, cefoxitin, cefotetan,cefuroxime, cefuroxime axetil; cefmetazole, cefprozil, loracarbef,ceforanide), third generation cephalosporins (e.g., cefepime,cefoperazone, cefotaxime, ceftizoxime, ceftriaxone, ceftazidime,cefixime, cefpodoxime, ceftibuten), other β-lactams (e.g., imipenem,meropenem, aztreonam, clavulanic acid, sulbactam, tazobactam, and thelike), betalactamase inhibitors (e.g., clavulanic acid),chlorampheriicol, macrolides (e.g., erythromycin, azithromycin,clarithromycin), lincomycin, clindamycin, spectinomycin, polymyxin B,polymixins (e.g., polymyxin A, B, C, D, E1 (colistin A), or E2, colistinB or C) colistin, vancomycin, telavancin, bacitracin, isoniazid,rifampin, ethambutol, ethionamide, aminosalicylic acid, cycloserine,capreomycin, sulfones (e.g., dapsone, sulfoxone sodium, and the like),clofazimine, thalidomide.

In one embodiment, the compound of Formula (I) or (II), orpharmaceutically acceptable salt of Formula (I) or (II), is administeredin combination with an aminoglycoside. In a further embodiment, thecompound is a compound of Formula (I) or Formula (I) wherein R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃. The aminoglycoside, in a further embodiment, isdibekacin, K-4619, sisomicin, amikacin, dactimicin, isepamicin,rhodestreptomycin, apramycin, etimicin, KA-5685, sorbistin, arbekacin,framycetin, kanamycin, spectinomycin, astromicin, gentamicin, neomycin,sporaricin, bekanamycin, H107, netilmicin, streptomycin, boholmycin,hygromycin, paromomycin, tobramycin, brulamycin, hygromycin B,plazomicin, verdamicin, capreomycin, inosamycin, ribostamycin orvertilmicin. In a further embodiment, the aminoglycoside is amikacin orgentamicin. In a further embodiment, the aminoglycoside is gentamicin.

Methods for treating bacterial infections, e.g., those caused byGram-positive microorganisms, are provided. Without wishing to be boundby a particular theory, it is believed that the R¹ groups conjugated tothe glycopeptides provided herein facilitate cellular uptake of theglycopeptide at the site of infection, for example, macrophage uptake.

In one embodiment, the infection is a Gram-positive cocci infection, forexample, a Staphylococcus, Enterococcus or Streptococcus infection.Streptococcus pneumoniae is treated, in one embodiment, in a patientthat has been diagnosed with community-acquired pneumonia or purulentmeningitis. An Enterococcus infection is treated, in one embodiment, ina patient that has been diagnosed with a urinary-catheter relatedinfection. A Staphylococcus infection, e.g., S. aureus is treated in oneembodiment, in a patient that has been diagnosed with mechanicalventilation-associated pneumonia.

Over the past few decades, there has been a decrease in thesusceptibility of Gram-positive cocci to antibacterials for thetreatment of infection. See, e.g., Alvarez-Lerma et al. (2006) Drugs 66,pp. 751-768, incorporated by reference herein in its entirety for allpurposes. As such, in one aspect, the present invention addresses thisneed by providing a composition comprising an effective amount of acompound of Formula (I), Formula (II) or a pharmaceutically acceptablesalt thereof, in a method for treating a patient in need thereof for aGram-positive cocci infection that is resistant to a differentantibacterial. For example, in one embodiment, the Gram-positive cocciinfection is a penicillin resistant or a vancomycin resistant bacterialinfection. In a further embodiment, the resistant bacterial infection isa methicillin-resistant Staphylococcus infection, e.g.,methicillin-resistant S. aureus or a methicillin-resistantStaphylococcus epidermidis infection. In another embodiment, theresistant bacterial infection is an oxacillin-resistant Staphylococcus(e.g., S. aureus) infection, a vancomycin-resistant Enterococcusinfection or a penicillin-resistant Streptococcus (e.g., S. pneumoniae)infection. In yet another embodiment, the Gram-positive cocci infectionis a vancomycin-resistant enterococci (VRE), methicillin-resistantStaphylococcus aureus (MRSA), methicillin-resistant Staphylococcusepidermidis (MRSE), vancomycin resistant Enterococcus faecium alsoresistant to teicoplanin (VRE Fm Van A), vancomycin resistantEnterococcus faecium sensitive to teicoplanin (VRE Fm Van B), vancomycinresistant Enterococcus faecalis also resistant to teicoplanin (VRE FsVan A), vancomycin resistant Enterococcus faecalis sensitive toteicoplanin (VRE Fs Van B), or penicillin-resistant Streptococcuspneumoniae (PSRP).

According to one embodiment, a method is provided to treat an infectiondue to a Gram-positive bacterium, including, but not limited to, generaStaphylococcus, Streptococcus, Enlerococcus, Bacillus, Corynebaclerium,Nocardia, Clostridium, and Listeria. In one embodiment, the infection isdue to a Gram-positive Cocci bacterium. In a further embodiment, theinfection is a pulmonary infection. In another embodiment, the infectionis a Clostridium difficile infection.

In even another embodiment, the bacterial infection is Propionibacteriumacnes (skin acne), Eggerthella lenta (bacteremia) or Peptostreptococcusanaerobius (gynecological infection). In a further embodiment, thecomposition administered to the patient in need thereof comprises acompound of Formula (I) or Formula (II) wherein R¹ is—(CH₂)₂—NH—(CH₂)₉—CH₃ and X is O.

Staphylococcus is Gram positive non-motile bacteria that colonizes skinand mucus membranes. Staphylococci are spherical and occur inmicroscopic clusters resembling grapes. The natural habitat ofStaphylococcus is nose; it can be isolated in 50% of normal individuals.20% of people are skin carriers and 10% of people harbor Staphylococcusin their intestines. Examples of Staphylococci infections treatable withthe methods and compositions provided herein, include S. aureus, S.epidermidis, S. auricularis, S. carnosus, S. haemolyticus, S. hyicus, S.intermedius, S. lugdunensis, S. saprophytics, S. sciuri, S. simulans,and S. warneri.

While there have been about 20 species of Staphylococcus reported, onlyStaphylococcus aureus and Staphylococcus epidermis are known to besignificant in their interactions with humans.

In one embodiment, the Staphylococcus species is resistant to apenicillin such as methicillin. In a further embodiment, theStaphylococcus species is methicillin-resistant Staphylococcus aureus(MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE). TheStaphylococcus infection, in another embodiment, is amethicillin-sensitive S. aureus (MSSA) infection, avancomycin-intermediate S. aureus (VISA) infection, or avancomycin-resistant S. aureus (VRSA) infection.

S. aureus colonizes mainly the nasal passages, but it may be foundregularly in most anatomical locales, including skin oral cavity, andgastrointestinal tract. In one embodiment, a S. aureus infection istreated with one of the methods and/or compositions provided herein. Ina further embodiment, the S. aureus infection is a methicillin-resistantStaphylococcus aureus (MRSA) infection. In another embodiment, the S.aureus infection is a S. aureus (VISA) infection, or avancomycin-resistant S. aureus (VRSA) infection.

The S. aureus infection can be a healthcare associated, i.e., acquiredin a hospital or other healthcare setting, or community-acquired.

In one embodiment, the Staphylococcal infection treated with one of themethods and/or compositions provided herein, causes endocarditis orsepticemia (sepsis). As such, the patient in need of treatment with oneof the methods and/or compositions provided herein, in one embodiment,is an endocarditis patient. In another embodiment, the patient is asepticemia (sepsis) patient.

In one embodiment, the bacterial infection is erythromycin-resistant(erm^(R)), vancomycin-intermediate S. aureus (VISA) heterogenousvancomycin-intermediate S. aureus (hVISA), S. epidermidiscoagulase-negative staphylococci (CoNS), penicillin-intermediate S.pneumoniae (PISP), or penicillin-resistant S. pneumoniae (PRSP). In evena further embodiment, the administering comprises administering viainhalation. In even a further embodiment, the compound of Formula (I) orFormula (II) is a compound wherein R¹ is —(CH₂)₂—NH—(CH₂)₉—CH₃ or

Streptococci are Gram-positive, non-motile cocci that divide in oneplane, producing chains of cells. The primary pathogens include S.pyrogenes and S. pneumoniae but other species can be opportunistic. S.pyrogenes is the leading cause of bacterial pharyngitis and tonsillitis.It can also produce sinusitis, otitis, arthritis, and bone infections.Some strains prefer skin, producing either superficial (impetigo) ordeep (cellulitis) infections.

S. pneumoniae is the major cause of bacterial pneumonia in adults, andin one embodiment, an infection due to S. pneumoniae is treated via oneof the methods and/or compositions provided herein. Its virulence isdictated by its capsule. Toxins produced by streptococci include:streptolysins (S & O), NADase, hyaluronidase, streptokinase, DNAses,erythrogenic toxin (which causes scarlet fever rash by producing damageto blood vessels; requires that bacterial cells are lysogenized by phagethat encodes toxin). Examples of Streptococcus infections treatable withthe compositions and methods provided herein include, S. agalactiae, S.anginosus, S. bovis, S. canis, S. constellatus, S. dysgalactiae, S.equi, S. equinus, S. Mae, S. intermedins, S. mitis, S. mutans, S.oralis, S. parasanguinis, S. peroris, S. pneumoniae, S. pyogenes, S.ratti, S. salivarius, S. salivarius ssp. thermophilics, S. sanguinis, S.sobrinus, S. suis, S. uteris, S. vestibularis, S. viridans, and S.zooepidemicus.

The genus Enterococci consists of Gram-positive, facultatively anaerobicorganisms that are ovoid in shape and appear on smear in short chains,in pairs, or as single cells. Enterococci are human pathogens that areincreasingly resistant to antimicrobial agents. Examples of Enterococcitreatable with the methods and compositions provided herein are E.avium, E. durans, E. faecalis, E. faecium, E. gallinarum, and E.solitarius.

In one embodiment of the methods provided herein, a patient in needthereof is treated for an Enterococcus faecalis (E. faecalis) infection.In a further embodiment, the infection is a pulmonary infection. Inanother embodiment, a patient in need thereof is treated for anEnterococcus faecium (E. faecium) infection. In a further embodiment,the infection is a pulmonary infection. In one embodiment, a patient inneed thereof is treated for an Enterococcus infection that is resistantor sensitive to vancomycin or resistant or sensitive to penicillin. In afurther embodiment, the infection is a E. faecalis or E. faeciuminfection.

Bacteria of the genus Bacillus are aerobic, endospore-forming,Gram-positive rods, and infections due to such bacteria are treatablevia the methods and compositions provided herein. Bacillus species canbe found in soil, air, and water where they are involved in a range ofchemical transformations. In one embodiment, a method is provided hereinto treat a Bacillus anthracis (B. anthracis) infection with aglycopeptide composition. Bacillus anthracis, the infection that causesAnthrax, is acquired via direct contact with infected herbivores orindirectly via their products. The clinical forms include cutaneousanthrax, from handling infected material, intestinal anthrax, fromeating infected meat, and pulmonary anthrax from inhaling spore-ladendust. The route of administration of the glycopeptide will varydepending on how the patient acquires the B. anthracis infection. Forexample, in the case of pulmonary anthrax, the patient, in oneembodiment, is treated via a dry powder inhaler (DPI), nebulizer ormetered dose inhaler (MDI).

Several other Bacillus species, in particular, B. cereus, B. subtilisand B. licheniformis, are associated periodically withbacteremia/septicemia, endocarditis, meningitis, and infections ofwounds, the ears, eyes, respiratory tract, urinary tract, andgastrointestinal tract, and are therefore treatable with the methods andcompositions provided herein. Examples of pathogenic Bacillus specieswhose infection is treatable with the methods and compositions providedherein, include, but are not limited to, B. anthracis, B. cereus and B.coagulans.

Corynebacteria are small, generally non-motile, Gram-positive, nonsporalating, pleomorphic bacilli and infections due to these bacteriaare treatable via the methods provided herein. Corynebacteriumdiphtheria is the etiological agent of diphtheria, an upper respiratorydisease mainly affecting children, and is treatable via the methodsprovided herein. Examples of other Corynebacteria species treatable withthe methods and compositions provided herein include Corynebacteriumdiphtheria, Corynebacterium pseudotuberculosis, Corynebacterium tenuis,Corynebacterium striatum, and Corynebacterium minutissimum.

The bacteria of the genus Nocardia are Gram-positive, partiallyacid-fast rods, which grow slowly in branching chains resembling fungalhyphae. Three species cause nearly all human infections: N. asteroides,N. brasiliensis, and N. caviae, and patients with such infections can betreated with the compositions and methods provided herein. Infection isby inhalation of airborne bacilli from an environmental source (soil ororganic material). Other Nocardial species treatable with the methodsprovided herein include N. aerocolonigenes, N. africana, N.argentinensis, N. asteroides, N. blackwellu, N. brasiliensis, N.brevicalena, N. cornea, N. caviae, N. cerradoensis, N. corallina, N.cyriacigeorgica, N. dassonvillei, N. elegans, N. farcinica, N.nigiitansis, N. nova, N. opaca, N. otitidis-cavarium, N. paucivorans, N.pseudobrasiliensis, N. rubra, N. transvelencesis, N. unif ormis, N.vaccinii, and N. veterana.

Clostridia are spore-forming, Gram-positive anaerobes, and infectionsdue to such bacteria are treatable via the methods and compositionsprovided herein. In one embodiment, one of the methods provided hereinare used to treat a Clostridium tetani (C. tetani) infection, theetiological agent of tetanus. In another embodiment, one of the methodsprovided herein is used to treat a Clostridium botidinum (C. botidinum)infection, the etiological agent of botulism. In yet another embodiment,one of the methods provided herein is used to treat a C. perfringensinfection, one of the etiological agents of gas gangrene. OtherClostridium species treatable with the methods of the present invention,include, C. difficile, C. perfringens, and/or C. sordelii. In oneembodiment, the infection to be treated is a C. difficile infection.

Listeria are non spore-forming, nonbranching Gram-positive rods thatoccur individually or form short chains. Listeria monocytogenes (L.monocytogenes) is the causative agent of listeriosis, and in oneembodiment, a patient infected with L. monocytogenes is treated with oneof the methods and compositions provided herein. Examples of Listeriaspecies treatable with the methods and compositions provided herein,include L. grayi, L. innocua, L. ivanovii, L. monocytogenes, L.seeligeri, L. murrayi, and L. welshimeri.

The bacterial infection in one embodiment, is a respiratory tractinfection. In a further embodiment, the infection is a resistantbacterial infection, for example, one of the infections provided above.The patient treatable by the methods provided herein, in one embodiment,has been diagnosed with a community-acquired respiratory tractinfection, e.g., pneumonia. In one embodiment, the bacterial infectiontreated in the pneumonia patient is a S. pneumoniae infection. Inanother embodiment, the bacterial infection treated in the pneumoniapatient is Mycoplasma pneumonia or a Legionella species. In anotherembodiment, the bacterial infection in the pneumonia patient ispenicillin resistant, e.g., penicillin-resistant S. pneumoniae.

The bacterial infection, in one embodiment, is a hospital acquiredinfection (HAI), or acquired in another health care facility, e.g., anursing home, rehabilitation facility, outpatient clinic, etc. Suchinfections are also referred to as nosocomial infections. In a furtherembodiment, the infection is a respiratory tract infection or a skininfection. In one embodiment, the HAI is pneumonia. In a furtherembodiment, the pneumonia is due to S. aureus, e.g., MRSA.

The inhalation delivery device employed in embodiments of the methodsprovided herein can be a nebulizer, dry powder inhaler (DPI), or ametered dose inhaler (MDI), or any other suitable inhalation deliverydevice known to one of ordinary skill in the art. The device can containand be used to deliver a single dose of the composition or the devicecan contain and be used to deliver multi-doses of the composition of thepresent invention.

According to one embodiment, a dry powder particulate composition isdelivered to a patient in need thereof via a metered dose inhaler (MDI),dry powder inhaler (DPI), atomizer, nebulizer or liquid doseinstillation (LDI) technique to provide for glycopeptide delivery. Withrespect to inhalation therapies, those skilled in the art willappreciate that where a hollow and porous microparticle composition isemployed, the composition is particularly amenable for delivery via aDPI. Conventional DPIs comprise powdered formulations and devices wherea predetermined dose of medicament, either alone or in a blend withlactose carrier particles, is delivered as an aerosol of dry powder forinhalation.

The medicament is formulated in a way such that it readily dispersesinto discrete particles with an MMD between 0.5 to 20 μm, for examplefrom 0.5-5 μm, and are further characterized by an aerosol particle sizedistribution less than about 10 μm mass median aerodynamic diameter(MMAD), and in some embodiments, less than 5.0 μm. The MMAD of thepowders will characteristically range from about 0.5-10 μm, from about0.5-5.0 μm, or from about 0.5-4.0 μm.

The powder is actuated either by inspiration or by some externaldelivery force, such as pressurized air. Examples of DPIs suitable foradministration of the particulate compositions of the present inventionare disclosed in U.S. Pat. Nos. 5,740,794, 5,785,049, 5,673,686, and4,995,385 and PCT application Nos. 00/72904, 00/21594, and 01/00263, thedisclosure of each of which is incorporated by reference in theirentireties for all purposes. DPI formulations are typically packaged insingle dose units such as those disclosed in the aforementioned patentsor they employ reservoir systems capable of metering multiple doses withmanual transfer of the dose to the device.

The compositions disclosed herein may also be administered to the nasalor pulmonary air passages of a patient via aerosolization, such as witha metered dose inhaler (MDI). Breath activated MDIs are also compatiblewith the methods provided herein.

Along with the aforementioned embodiments, the compositions disclosedherein may be delivered to a patient in need thereof via a nebulizer,e.g., a nebulizer disclosed in PCT WO 99/16420, the disclosure of whichis hereby incorporated in its entirety by reference, in order to providean aerosolized medicament that may be administered to the pulmonary airpassages of the patient. A nebulizer type inhalation delivery device cancontain the compositions of the present invention as a solution, usuallyaqueous, or a suspension. For example, the prostacyclin compound orcomposition can be suspended in saline and loaded into the inhalationdelivery device. In generating the nebulized spray of the compositionsfor inhalation, the nebulizer delivery device may be drivenultrasonically, by compressed air, by other gases, electronically ormechanically (e.g., vibrating mesh or aperture plate). Vibrating meshnebulizers generate fine particle, low velocity aerosol, and nebulizetherapeutic solutions and suspensions at a faster rate than conventionaljet or ultrasonic nebulizers. Accordingly, the duration of treatment canbe shortened with a vibrating mesh nebulizer, as compared to a jet orultrasonic nebulizer. Vibrating mesh nebulizers amenable for use withthe methods described herein include the Philips Respironics I-Neb®, theOmron MicroAir, the Nektar Aeroneb®, and the Pari eFlow®.

The nebulizer may be portable and hand held in design, and may beequipped with a self contained electrical unit. The nebulizer device maycomprise a nozzle that has two coincident outlet channels of definedaperture size through which the liquid formulation can be accelerated.This results in impaction of the two streams and atomization of theformulation. The nebulizer may use a mechanical actuator to force theliquid formulation through a multiorifice nozzle of defined aperturesize(s) to produce an aerosol of the formulation for inhalation. In thedesign of single dose nebulizers, blister packs containing single dosesof the formulation may be employed.

In the present invention, the nebulizer may be employed to ensure thesizing of particles is optimal for positioning of the particle within,for example, the pulmonary membrane.

Upon nebulization, the nebulized composition (also referred to as“aerosolized composition”) is in the form of aerosolized particles. Theaerosolized composition can be characterized by the particle size of theaerosol, for example, by measuring the “mass median aerodynamicdiameter” or “fine particle fraction” associated with the aerosolizedcomposition. “Mass median aerodynamic diameter” or “MMAD” is normalizedregarding the aerodynamic separation of aqua aerosol droplets and isdetermined by impactor measurements, e.g., the Andersen Cascade Impactor(ACI) or the Next Generation Impactor (NGI). The gas flow rate, in oneembodiment, is 8 Liter per minute for the ACI and 15 liters per minutefor the NGI.

“Geometric standard deviation” or “GSD” is a measure of the spread of anaerodynamic particle size distribution. Low GSDs characterize a narrowdroplet size distribution (homogeneously sized droplets), which isadvantageous for targeting aerosol to the respiratory system. Theaverage droplet size of the nebulized composition provided herein, inone embodiment is less than 5 μm or about 1 μm to about 5 μm, and has aGSD in a range of 1.0 to 2.2, or about 1.0 to about 2.2, or 1.5 to 2.2,or about 1.5 to about 2.2.

“Fine particle fraction” or “FPF,” as used herein, refers to thefraction of the aerosol having a particle size less than 5 μm indiameter, as measured by cascade impaction. FPF is usually expressed asa percentage.

In one embodiment, the mass median aerodynamic diameter (MMAD) of thenebulized composition is about 1 μm to about 5 μm, or about 1 μm toabout 4 μm, or about 1 μm to about 3 μm or about 1 μm to about 2 μm, asmeasured by the Anderson Cascade Impactor (ACI) or Next GenerationImpactor (NGI). In another embodiment, the MMAD of the nebulizedcomposition is about 5 μm or less, about 4 μm or less, about 3 μm orless, about 2 μm or less, or about 1 μm or less, as measured by cascadeimpaction, for example, by the ACI or NGI.

In one embodiment, the MMAD of the aerosol of the pharmaceuticalcomposition is less than about 4.9 μm, less than about 4.5 μm, less thanabout 4.3 μm, less than about 4.2 μm, less than about 4.1 μm, less thanabout 4.0 μm or less than about 3.5 μm, as measured by cascadeimpaction.

In one embodiment, the MMAD of the aerosol of the pharmaceuticalcomposition is about 1.0 μm to about 5.0 μm, about 2.0 μm to about 4.5μm, about 2.5 μm to about 4.0 μm, about 3.0 μm to about 4.0 μm or about3.5 μm to about 4.5 μm, as measured by cascade impaction (e.g., by theACI or NGI).

In one embodiment, the FPF of the aerosolized composition is greaterthan or equal to about 50%, as measured by the ACI or NGI, greater thanor equal to about 60%, as measured by the ACI or NGI or greater than orequal to about 70%, as measured by the ACI or NGI. In anotherembodiment, the FPF of the aerosolized composition is about 50% to about80%, or about 50% to about 70% or about 50% to about 60%, as measured bythe NGI or ACI.

In one embodiment, a metered dose inhalator (MDI) is employed as theinhalation delivery device for the compositions of the presentinvention. In a further embodiment, the prostacyclin compound issuspended in a propellant (e.g., hydrofluorocarbon) prior to loadinginto the MDI. The basic structure of the MDI comprises a metering valve,an actuator and a container. A propellant is used to discharge theformulation from the device. The composition may consist of particles ofa defined size suspended in the pressurized propellant(s) liquid, or thecomposition can be in a solution or suspension of pressurized liquidpropellant(s). The propellants used are primarily atmospheric friendlyhydroflourocarbons (HFCs) such as 134a and 227. The device of theinhalation system may deliver a single dose via, e.g., a blister pack,or it may be multi dose in design. The pressurized metered doseinhalator of the inhalation system can be breath actuated to deliver anaccurate dose of the lipid-containing formulation. To insure accuracy ofdosing, the delivery of the formulation may be programmed via amicroprocessor to occur at a certain point in the inhalation cycle. TheMDI may be portable and hand held.

In one embodiment, a dry powder inhaler (DPI) is employed as theinhalation delivery device for the compositions of the presentinvention.

In one embodiment, the DPI generates particles having an MMAD of fromabout 1 μm to about 10 μm, or about 1 μm to about 9 μm, or about 1 μm toabout 8 μm, or about 1 μm to about 7 μm, or about 1 μm to about 6 μm, orabout 1 μm to about 5 μm, or about 1 μm to about 4 μm, or about 1 μm toabout 3 μm, or about 1 μm to about 2 μm in diameter, as measured by theNGI or AC. In another embodiment, the DPI generates particles having anMMAD of from about 1 μm to about 10 μm, or about 2 μm to about 10 μm, orabout 3 μm to about 10 μm, or about 4 μm to about 10 μm, or about 5 μmto about 10 μm, or about 6 μm to about 10 μm, or about 7 μm to about 10μm, or about 8 μm to about 10 μm, or about 9 μm to about 10 μm, asmeasured by the NGI or ACI.

In one embodiment, the MMAD of the particles generated by the DPI isabout 1 μm or less, about 9 μm or less, about 8 μm or less, about 7 μmor less, 6 μm or less, 5 μm or less, about 4 μm or less, about 3 μm orless, about 2 μm or less, or about 1 μm or less, as measured by the NGIor ACI.

In one embodiment, each administration comprises 1 to 5 doses (puffs)from a DPI, for example 1 dose (1 puff), 2 dose (2 puffs), 3 doses (3puffs), 4 doses (4 puffs) or 5 doses (5 puffs). The DPI, in oneembodiment, is small and transportable by the patient.

In one embodiment, the MMAD of the particles generated by the DPI isless than about 9.9 μm, less than about 9.5 μm, less than about 9.3 μm,less than about 9.2 μm, less than about 9.1 μm, less than about 9.0 μm,less than about 8.5 μm, less than about 8.3 μm, less than about 8.2 μm,less than about 8.1 μm, less than about 8.0 μm, less than about 7.5 μm,less than about 7.3 μm, less than about 7.2 μm, less than about 7.1 μm,less than about 7.0 μm, less than about 6.5 μm, less than about 6.3 μm,less than about 6.2 μm, less than about 6.1 μm, less than about 6.0 μm,less than about 5.5 μm, less than about 5.3 μm, less than about 5.2 μm,less than about 5.1 μm, less than about 5.0 μm, less than about 4.5 μm,less than about 4.3 μm, less than about 4.2 μm, less than about 4.1 μm,less than about 4.0 μm or less than about 3.5 μm, as measured by the NGIor ACI.

In one embodiment, the MMAD of the particles generated by the DPI isabout 1.0 μm to about 10.0 μm, about 2.0 μm to about 9.5 μm, about 2.5μm to about 9.0 μm, about 3.0 μm to about 9.0 μm, about 3.5 μm to about8.5 μm or about 4.0 μm to about 8.0 μm.

In one embodiment, the FPF of the prostacyclin particulate compositiongenerated by the DPI is greater than or equal to about 40%, as measuredby the ACI or NGI, greater than or equal to about 50%, as measured bythe ACI or NGI, greater than or equal to about 60%, as measured by theACI or NGI, or greater than or equal to about 70%, as measured by theACI or NGI. In another embodiment, the FPF of the aerosolizedcomposition is about 40% to about 70%, or about 50% to about 70% orabout 40% to about 60%, as measured by the NGI or ACI.

EXAMPLES

The present invention is further illustrated by reference to thefollowing Examples. However, it should be noted that these Examples,like the embodiments described above, are illustrative and are not to beconstrued as restricting the scope of the invention in any way.

Example 1—Synthesis of Glycopeptide Derivative Via Reductive Amination

Glycopeptide derivatives were prepared as follows. The synthesis schemeis also provided at FIG. 1.

To a reactor vessel equipped with temperature control and agitation wasadded anhydrous DMF and DIPEA. The resulting solution was heated to 65°C. with agitation and Vancomycin HCl or telavancin HCl was added slowlyin portions. Heating was continued until all of vancomycin HCl ortelavancin HCl had dissolved (5-10 min).

The beige colored solution was allowed to cool after which a solution ofthe desired aldehyde dissolved in DMF was added over 5-10 min. Theresulting solution was allowed to stir overnight, typically producing aclear red-yellow solution. MeOH and TFA were introduced and stirring wasfurther continued for at least 2 h. At the end of the stirring period,the imine forming reaction mixture was analyzed by HPLC which wascharacteristically typical. Borane tert-butylamine complex was added inportions and the reaction mixture was stirred at ambient temperature foran additional 2 h after which an in-process HPLC analysis of thereaction mixture indicated a near quantitative reduction of theintermediate imine group. After the reaction was over, the reactionmixture was purified using reverse phase C18 column chromatography(Phenomenex Luna 10 uM PREP C18(2) 250×21.2 mm column) using gradientsof water and acetonitrile, each containing 0.1% (v/v) of TFA. Fractionswere evaluated using HPLC and then pertinent fractions containing thetarget product were pooled together for the isolation of the product vialyophilization. Typical products were isolated as fluffy white solids.The procedure is shown below in Scheme 1 with vancomycin HCl as arepresentative starting compound.

Example 2—Synthesis of Vancomycin Derivative RV40 (Compound 40)

General Synthesis:

To a temperature controlled reactor vessel equipped with an overheadstirrer was added a suitable reaction solvent (DMF or DMA) and anorganic base (typically DIPEA). The temperature was increased toapproximately 60° C. and vancomycin HCl was added. The warm reactionmixture was agitated at elevated temperature for approximately 20minutes at which point all vancomycin HCl had dissolved and the reactionmixture was returned to room temperature. To the reaction mixture wasthen added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate(N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reactionsolvent (DMF or DMA). The reaction mixture was agitated with an overheadstirrer overnight at which point a suitable reducing agent, acidcatalyst (e.g., TFA), and a protic solvent (e.g., MeOH) were added. Thereaction mixture was agitated by an overhead stirrer at room temperaturefor approximately two hours at which point solvent volume was reduced byhalf via rotary evaporation. To the concentrated reaction mixture wasthen added an organic base to remove the FMOC protecting group and yieldcrude product (Compound 40, also referred to as “RV40”, see also Table1). Solvent was then evaporated by rotary evaporation and the crudematerial was dry-packed using C18 silica and purified via reverse phaseC18 flash chromatography to isolate product with >97% purity. Solventwas removed from the purified material using a combination of techniquesincluding rotary evaporation, lyophilization, and spray drying to yieldproduct (Compound 40 or RV40) as a white powder, typically in 40-75%overall yield. Suitable solvents include N,N-Dimethylacetamide,N,N-Dimethylformamide, N,N-Dimethylacetamide or a combination thereof.Suitable organic bases include N,N-diisopropylethylamine ortrimethylamine. Suitable reducing agents include NaBH₄, NaBH₃CN,Borane-pyridine complex, or Borane-^(tert)butylamine complex. Suitableorganic bases for FMOC deprotection include piperidine, methylamine, and^(tert)butylamine.

Salt Forms:

Control over the salt form and associated counter-ions foralkyl-vancomycin derivatives was managed by altering the acid speciesused during flash chromatography. Lactate, Acetate, HCl, and TFA saltshave been prepared. To isolate free base derivatives of alkyl vancomycinderivatives the pH of purified material was adjusted between 7-8 toinduce precipitation; purified free base material was then collected byfiltration, rotary evaporation, lyophilization, or spray drying.

One synthetic scheme for arriving at compound 40 (RV40) is provided atFIG. 2 (top). Here, a jacketed 1 L reactor vessel was equipped with anoverhead stirrer and connected to a recirculating water bath calibratedto 65° C. To the warm reaction vessel was added N,N-Dimethylformamide(75 mL) and DIPEA (640 μL, 3.7 mmol, 2.0 equivalents). Solvent wasallowed to stir for 20 minutes and warmed to 65° C., at which pointvancomycin HCl (2.70 g, 1.8 mmol, 1.00 equivalents) was added to thereaction mixture. Once all vancomycin HCl had dissolved the temperaturewas reduced to 25° C. and 9H-fluoren-9-ylmethylN-decyl-N-(2-oxoethyl)carbamate (890 mg, 2.1 mmol, 1.15 equivalents)dissolved in N,N-Dimethylformamide (20 mL) was added. The reactionmixture was allowed to stir at 25° C. for 18 hrs. To the reactionmixture was then added NaBH₃CN (330 mg, 5.3 mmol, 2.89 equivalents),MeOH (75 mL), and TFA (3.0 mL, 5.5 mmol, 3.00 equivalents). The reactionmixture was allowed to stir for 3 hr at RT at which point solvent volumewas reduced by half via rotary evaporation. To the concentrated reactionmixture was then added piperidine (360 μL, 3.7 mmol, 2.00 equivalents)with stirring. Reaction progress was monitored by HPLC. Once HPLCanalysis indicated complete deprotection, solvent was removed from thereaction mixture under reduced pressure to yield crude product (Compound40) as an off-white solid. The crude material was dry-packed using C18silica and purified via reverse phase C18 flash chromatography toisolate product with >97% purity.

Example 3—Synthesis of Vancomycin Derivative RV40 (Compound 40)

General Synthesis:

To a temperature controlled reactor vessel equipped with an overheadstirrer was added a suitable reaction solvent (DMF or DMA) and anorganic base (typically DIPEA). The temperature was increased toapproximately 60° C. and vancomycin HCl was added. The warm reactionmixture was agitated at elevated temperature for approximately 20minutes at which point all vancomycin HCl had dissolved and the reactionmixture was returned to room temperature. To the reaction mixture wasthen added 9H-fluoren-9-ylmethyl N-decyl-N-(2-oxoethyl)carbamate(N-Fmoc-N-decylaminoacetaldehyde) dissolved in a suitable reactionsolvent (DMF or DMA). The reaction mixture was agitated with an overheadstirrer overnight. To the reaction mixture was added a protic solvent(e.g., MeOH) and an acid catalyst (e.g., TFA) and the reaction mixturewas allowed to stir for 15 minutes prior to addition of a suitablereducing agent (e.g., borane tertbutylamine complex).

The reaction mixture was agitated by an overhead stirrer at roomtemperature for approximately two hours at which point an organic base(e.g., tertbutylamine) was added to remove the FMOC protecting group.The temperature was increased to 55° C. and the mixture was allowed tostir for 2 h. Solvent was then evaporated by rotary evaporation and thecrude material was dry-packed using C18 silica and purified via reversephase C18 flash chromatography to isolate product with >97% purity.Solvent was removed from the purified material using a combination oftechniques including rotary evaporation, lyophilization, and spraydrying to yield product (RV40) as a white powder, typically in 75%overall yield. Suitable solvents include N,N-Dimethylacetamide,N,N-Dimethylformamide, N,N-Dimethylacetamide or a combination thereof.Suitable organic bases include N,N-diisopropylethylamine ortrimethylamine. Suitable reducing agents include NaBH₄, NaBH₃CN,Borane-pyridine complex, or Borane-^(tert)butylamine complex. Suitableorganic bases for FMOC deprotection include piperidine, methylamine, and^(tert)butylamine.

Salt Forms:

Control over the salt form and associated counter-ions foralkyl-vancomycin derivatives was managed by altering the acid speciesused during flash chromatography. Lactate, Acetate, HCl, and TFA saltshave been prepared. To isolate free base derivatives of the vancomycinderivative, the pH of purified material was adjusted between 7-8 toinduce precipitation; purified free base material was then collected byfiltration, rotary evaporation, lyophilization, or spray drying.

One synthetic scheme for arriving at compound 40 (RV40) is provided atFIG. 2, bottom, and is described in further detail below. To a 400 mLreactor vessel equipped with an overhead stirrer, a thermometer, and apH meter was added DMF (50 mL) and DIPEA (1.17 mL, 6.73 mmol, 2.00equivalents). The reaction mixture was heated to 55° C. at which pointvancomycin HCl (5.0 g, 3.37 mmol, 1.0 equivalents) were added. Themixture was stirred at 55° C. for about 15 min., or until all of thevancomycin dissolved, at which point the temperature was reduced to 25°C. To the reaction mixture was added a solution ofN-Fmoc-decylaminoacetaldehyde (1.63 g, 3.87 mmol, 1.15 equivalents)dissolved in DMF (16.32 mL). The reaction mixture was allowed to stir at25° C. for 18 h. To the reaction mixture was added MeOH (14.0 mL) andTFA (1.03 mL, 13.46 mmol, 4.00 equivalent) and the mixture was allowedto stir at 25° C. for 15 min., at which point Borane tert-butylaminecomplex (294 mg, 3.37 mmol, 1.0 equivalents) were added. The reactionmixture was allowed to stir at 25° C. for 2 h, at which pointtert-butylamine (4.24 mL, 40.38 mmol, 12.0 equivalents) was added, andthe temperature was increased to 55° C. The reaction mixture was allowedto stir at 55° C. for 2 h. C18 functionalized silica gel was then addedto the reaction mixture and solvent was removed under reduced pressure.The dry-packed material was purified using reverse phase C18 flashchromatography (Biotage® SNAP-KP-C18-HS column).

Example 4—Preparation of Monolactate Salt of RV40

A 3 L three-necked flask was equipped with a mechanical stirrer, anitrogen inlet, a condenser and an addition funnel. Anhydrous DMF (900mL) and DIPEA (21.06 mL, 0.12 mol) were charged. The resulting solutionwas heated to 55-60° C. and vancomycin HCl (90.0 g, 0.06 mol) was addedin portions. Heating was continued until all of vancomycin HCl haddissolved (15-30 min). The beige colored solution was allowed to cool toambient temperature after which a solution ofN—FMOC—N-decylaminoacetaldehyde (29.34 g, 0.069 mol) and DMF (293.4 mL)was added via the addition funnel over 5-10 min. The resulting solutionwas allowed to stir overnight to give a clear red-yellow solution. Anin-process HPLC analysis of the reaction mixture at the end of thestirring period was typical. MeOH (252 mL) and TFA (18.54 mL, 0.24 mol)were introduced and stirring was further continued for at least 2 h. Atthe end of the stirring period, the imine forming reaction mixture wasanalyzed by HPLC which was characteristically typical. Boranetert-butylamine complex (5.28 g, 0.61 mol) was added in portions and thereaction mixture was stirred at ambient temperature for an additional 2h after which an in-process HPLC analysis of the reaction mixtureindicated a near quantitative reduction of the intermediate imine groupwith less than 3% of the unreacted vancomycin remaining. Tert-Butylamine(76.32 mL, 0.73 mol) was added via the addition funnel and the resultingreaction was heated to 55° C. The stirring was continued at 55° C. andprogress of the FMOC group deprotection reaction was monitored by HPLC.

After the reaction was over (about 2 h), heating was removed and C18silica gel (C-18 (Carbon 17%) 60A, 40-63 μm, 270 g) was added and themixture was concentrated on a rotavap at 52° C./15 torr untilfree-flowing solids of C-18 silica adsorbed crude RV40 were obtained(3-7 h). The C-18 silica adsorbed crude RV40 (compound 40) was dividedinto three equal parts and each part-lot was purified by means ofBiotage chromatography on a Biotage SNAP ULTRA C18 1850 g Cartridge(Biotage HP-Sphere C18 25 μm) using gradients of water and acetonitrile,each containing 0.1% (v/v) of an 85% L-(+)-Lactic acid solution inwater, and collecting 240 mL fractions. Each part lot required 50 litersof eluents. After each Biotage run, the C-18 column was conditioned forthe next run by running through 60 liters of methanol. Fractions wereevaluated using HPLC and then pertinent fractions containing RV40 werepooled together for the isolation of the product via lyophilization.

Lyophilization provided RV40 lactate salt as a white solid. Thelyophilized RV40 lactate at this point typically contained excess lacticacid and also contained lactic acid related impurities arising from itsself-condensation reactions. The isolated RV40 lactate from this run wascombined with two other batches of similarly isolated lyophilized RV40lactate to form a composite batch of RV40 lactate totaling 105 g (lot637-140A). The excess lactic acid and its related impurities present inthe above composite batch of RV40 lactate were removed via triturationwith THF and then the final triturated material (RV40 mono lactatesalts) was subjected to re-lyophilization to remove the trapped residualTHF; both steps are described below.

A 5 L three-necked flask was equipped with a mechanical stirrer, anitrogen inlet, and a condenser. RV40 lactate salts (105 g) andinhibitor-free anhydrous THF (1 L) were charged. The resulting mixturewas stirred under nitrogen. After stirring overnight, the resultingmixture was filtered using a medium frit Buchner filter funnel. Thefiltered cake was washed with THF (250 mL). The filtered cake was driedon the filter funnel by pulling vacuum under nitrogen. After drying for5 h the cake was analyzed by 1H NMR for the residual levels of lacticacid which were measured as 3.5 equivalents. The process of triturationwith THF was repeated two more times after which the isolated productwas determined to contain estimated 1 equivalent of lactic acid/lactateand THF. The isolated material was re-lyophilized to remove the residualTHF as follows:

The above THF-triturated material was first dissolved in aqueousacetonitrile (3:1 water:acetonitrile) at a concentration of 8.1 mL pergram and then lyophilized in batches using multiple flasks. Typically,about 10-12 grams (maximum) of the material was charged into each 2 Lflask followed by aqueous acetonitrile (125 mL) to prepare a solutionwhich was lyophilized. At the end of the lyophilization and drying,product was analyzed by NMR for THF levels to determine whetherlyophilization was needed to be repeated. In the current case, contentsof each flask were lyophilized once more (after re-dissolving in 125 mLof aqueous acetonitrile) when no remaining THF could be detected by NMR.The final lyophilized product at this point contained an average of 0.8wt. % acetonitrile as estimated by NMR. The contents of each flask werepulverized into smaller particles using spatula and then placed on highvacuum pumps to remove acetonitrile. No further reduction inacetonitrile levels was observed after 56-60 h on the vacuum pumps.Contents of each flasks were combined to provide a total of 74.3 g(35.5% yield based on the total conversion of 180 g of vancomycin HCl)of a composite batch of RV40 mono lactate salts as white solid which wasfound to be >99 area % pure by HPLC and contained one equivalent oflactate as determined by 1HNMR (DMSO-d6) analysis. The water content inthe product was found at 5.6 wt. % as determined by K—F analysis.

Example 5—Synthesis of Vancomycin Derivative RV79

The synthesis scheme for arriving at the glycopeptide derivative RV79 isdescribed below, and also provided at FIG. 3. To a 40 mL vial equipped astir bar was added anhydrous DMF (20 mL) and DIPEA (0.20 mL). Theresulting solution was heated to 65° C. on an incubated shaker andvancomycin HCl (700 mg, 0.462 mmol) was added slowly in portions.Heating was continued until all of vancomycin HCl had dissolved (5-10min). The beige colored solution was allowed to cool to room temperatureat which point 4′-Chloro-biphenyl-4-carbaldehyde (0.1 g, 0.462 mmol) wasadded to the reaction mixture. The reaction mixture was allowed to stirovernight. MeOH (1.5 mL) and TFA (0.14 mL, 1.8 mmol) were introduced andstirring was further continued for at least 2 h. Borane tert-butylaminecomplex (40 mg, 0.46 mmol) was added in portions and the reactionmixture was stirred at ambient temperature for an additional 2 h. Afterthe reaction completed, the reaction mixture is purified using reversephase C18 column chromatography (Phenomenex Luna 10 uM PREP C18(2)250×21.2 mm column) using gradients of water and acetonitrile, eachcontaining 0.1% (v/v) of TFA. Fractions were evaluated using HPLC andthen pertinent fractions containing RV79 were pooled together forisolation of the product via lyophilization. The target compound, RV79(81.2 mg, 0.05 mmol, 10% overall yield), was obtained as a white solidin >97% purity (by HPLC). The reaction scheme is shown at FIG. 3.

Example 6—Synthesis of Alkyl-Vancomycin Derivatives

Alkyl vancomycin derivatives were prepared according to the proceduredisclosed in Nagarajan et al., with slight modifications (Nagarajan etal. (1989). The Journal of Antibiotics 42(1), pp. 63-72, incorporated byreference herein in its entirety for all purposes).

The general synthesis for alkyl vancomycin derivatives is shown in FIG.4. Briefly, to a temperature controlled reactor vessel was addedvancomycin HCl, a suitable reaction solvent, an organic base, and theappropriate aldehyde. The reaction mixture was agitated with an overheadstirrer at elevated temperature and reaction progress was monitored viaHPLC looking at consumption of vancomycin and imine formation. To thereactor vessel was then added a suitable reducing agent, acid catalyst(TFA), and a protic solvent (MeOH). The reaction mixture was agitated byan overhead stirrer for approximately 2 h. The reaction mixture was theneither poured into water to induce precipitation of the alkyl vancomycinderivative, or solvent was removed under reduced pressure.

The crude material was dissolved in a suitable mobile phase and purifiedvia preparative chromatography. Solvent was removed from the purifiedmaterial using a combination of techniques including rotary evaporation,lyophilization, and spray drying to yield the vancomycin alkylderivative as a white powder, typically in 40-60% overall yield.Suitable solvents include either N,N-Dimethylformamide orN,N-Dimethylacetamide. Suitable organic bases includeN,N-diisopropylethylamine or trimethylamine. Suitable reducing agentsinclude NaBH₄, NaBH₃CN, Borane-pyridine complex, orBorane-^(tert)butylamine complex.

Synthesis of N-Decyl Vancomycin (Compound 5):

The synthetic route to Compound 5, decyl vancomycin, is provided at FIG.5. A jacketed 1 L reactor vessel was equipped with an overhead stirrerand connected to a recirculating water bath calibrated to 65° C. To thewarm reaction vessel was added N,N-Dimethylacetamide (160 mL) and DIPEA(6.8 mL, 39.0 mmol, 2.92 equivalents), the solvents were allowed to stirfor approximately 20 minutes. Once the solvent temperature had reached65° C., vancomycin HCl (19.8 g, 13.38 mmol, 1.00 equivalents) was addedto the reactor vessel. To the reactor vessel was added 1-Decanal (2.54mL, 13.50 mmol, 1.01 equivalents) and the reaction mixture was allowedto stir for 2 hours at 65 C°. To the reaction mixture was then addedNaBH₃CN (2.31 g, 36.77 mmol, 2.75 equivalents), MeOH (100 mL), and TFA(3.1 mL, 40.48 mmol, 3.03 equivalents). The reaction mixture was allowedto stir for 2 hours while cooling to room temperature. The reactionmixture was then poured into acetonitrile (1 L) to induce precipitation.The decant was removed and the remaining off-white slurry wascentrifuged and decanted to remove excess solvent and produce a slurrycontaining N-decyl vancomycin and unreacted vancomycin. Crude N-decylvancomycin as dissolved in 30:70 acetonitrile:H₂O with 0.05% HOAc andpurified using reverse phase C18 preparative HPLC. Pure fractions weresubjected to rotary evaporation to remove organics and the flash-frozenand lyophilized to isolate purified N-decyl vancomycin as a fluffy whitepowder.

Example 7—Synthesis of Chloroeremomycin Derivative RV79

To a 20 mL scintillation vial equipped with a stir bar was addedchloroeremomycin and a solution of copper (II) acetate in MeOH. Thereaction mixture was stirred at room temperature until thechloroeremomycin had dissolved. To the reaction mixture was then addedthe appropriate aldehyde and sodium cyanoborohydride as a 1M solution inTHF. The reaction mixture was transferred to an incubated shaker set to45° C. and reaction progress was monitored by HPLC. In some instances,it was necessary to add an additional aliquot of aldehyde reagent. Thereaction mixture was allowed to shake overnight at 45° C. The reactionmixture was cooled to RT and sodium borohydride was added to convertresidual aldehyde reagent to the corresponding alcohol. The pH wasadjusted to between 7-8 using either acetic acid or 0.1M NaOH andvolatile solvents were removed by blowing N₂(g) with gentle heat. To thereaction mixture was added acetonitrile to precipitate the crude productas an off-white solid. The reaction mixture was centrifuged and theliquid was decanted. The solid was dissolved in 10% MeCN/H₂O containing0.1% phosphoric acid to decomplex the copper at which point the solutionbriefly turned purple and then took on a yellow tinge. Preparatory HPLCwas used to purify final product and LCMS was used to confirm compoundidentity and purity.

A diagram of the reaction is provided at FIG. 1, bottom.

Example 8—C-terminus Modification of Glyconentide Derivative

To a round bottom flask equipped with a stir bar was added a LPGCderivative, a 1:1 solution of DMF:DMSO, and DIPEA. To the reactionmixture was then added HBTU and the appropriate amine (e.g.,3-(dimethylamino)-1-propylamine). Reaction progress was monitored byHPLC. Once complete, the reaction was quenched upon addition of 1:1H₂O:MeOH. The crude material was then purified using reverse phase C18preparatory HPLC. Purified fractions were lyophilized to yield thetarget products, typically as a white fluffy powder in modest yield andhigh purity.

Example 9—Resorcinol-Like Modification of Glycopeptide Derivative

To a round bottom flask equipped with a stir bar was added(Aminomethyl)phosphoric acid, water, and DIPEA. The reaction mixture wasallowed to stir for 15 minutes at room temperature. To the reactionmixture was then added acetonitrile and formaldehyde, 37% solution inH₂O. The reaction mixture was allowed to stir for an additional 15 min.at which point a glycopeptide derivative and additional DIPEA wereadded. Reaction progress was closely monitored using HPLC. Once completethe reaction mixture was purified using reverse phase C18 preparativeHPLC. Purified fractions were lyophilized to yield the target product asa white fluffy powder.

Example 10—Minimum Inhibitory Concentration (MIC) of GlycopeptideDerivatives

MIC Testing: Glycopeptide compounds were dissolved in 100% DMSO. Invitro activities were determined using CLSI-guided broth susceptibilitytesting to measure drug minimum inhibitory concentrations (MICs) of thecompounds against the quality control strain ATCC 29213 (MSSA) and theMRSA isolate ATCC BAA-1556. The minimal inhibitory concentrations MICsare summarized in Table 2. Glycopeptides are defined as compounds ofFormula (I), and their respective R¹, R², R³ and R⁴ groups. X is —O— foreach compound in Table 2.

TABLE 2 MIC Values μg/mL MRSA MRSA Glycopeptide Structure (Formula (I))CMPD 1556 29213 R¹ R² R³ R⁴ RV41 0.063 0.031 (CH₂)₉CH₃ H H H RV57 0.2500.125 (CH₂)₇CH₃ H H H RV58 1.000 1.000 (CH₂)₅CH₃ H H H RV79 0.016 0.016

H H H RV84 1.000 1.000 (CH2)₂NH(CH₂)₉CH₃ H H

RV85 0.125 0.125 (CH₂)₉CH₃ H H

RV45 0.063 0.125 (CH₂)₂NH(CH₂)₉CH₃ H NH(CH₂)₃N(CH₃)₂ H Tela- 0.063 0.063(CH₂)₂NH(CH₂)₉CH₃ CH₂—NH—CH₂—PO₃H₂ H H vancin

Example 11—In Vitro Activity of Glycopeptide Agents Against GramPositive Bacteria

The susceptibility of a variety of Staphylococcus aureus, includingreference methicillin-resistant (MRSA) and vancomycin-intermediate(VISA) isolates to various antibiotic compounds was assessed.

Broth microdilution MIC testing was conducted in accordance withguidelines from the Clinical and Laboratory Standards Institute (CLSI;1, 2) and included the comparators telavancin (TLV), vancomycin (VAN),tigecycline (TGC), and linezolid (LNZ). In addition, the susceptibilityof other Gram-positive bacteria (Enterococci, Streptococci, andClostridium difficile) to the test agents and comparators was alsodetermined.

Materials and Methods

Test compounds. The 6 test agents and the comparators are detailed inTable 3 below.

TABLE 3 Test compounds Stock Solution Compound Solvent/Diluent μg/mLCompound 5 DMSO 6400 Compound 40 (RV40) DMSO 3200-6400 Telavancin (TLV)DMSO  800 Tigecycline (TGC) H₂O  800-3200 Vancomycin (VAN) H₂O 6400Linezolid (LNZ) H₂O 1600 Oritavancin (ORI) 0.002% P80  800 DMSO:Dimethyl sulfoxide (Sigma, St. Louis, MO; Cat. No. 472301) P80:Polysorbate-80 (Spectrum, New Brunswick, NJ; Cat. No. P0138)

Isolates.

The test organisms were originally received from clinical sources, theAmerican Type Culture Collection (ATCC, Manassas, Va.), and the Networkon Antimicrobial Resistance in S. aureus (NARSA; BEI Resources,Manassas, Va.). Upon receipt, the organisms were sub-cultured onto anappropriate agar medium. Following incubation, colonies were harvestedfrom these plates and cell suspensions prepared and frozen at −80° C.with a cryoprotectant. On the day prior to the assay, frozen stocks ofisolates were streaked onto Trypticase Soy Agar with 5% sheep blood(Remel, Lenexa, Kans.; Lot No. 964323) and incubated overnight at 35° C.in ambient atmosphere, with the exception of Streptococci which wereincubated overnight at 35° C. in 5% CO₂, and C. difficile which wasstreaked onto Brucella Agar (Becton Dickinson, Sparks, Md.; Lot No.6168880) and incubated anaerobically at 35° C. for 48 h.

The following S. aureus isolates and associated phenotypes wereevaluated against the aforementioned antibiotics (Table 4).

TABLE 4 MIC (μg/mL) Organism Isolate No. Phenotype LNZ* VAN* TCG* ORI #5TLV #40* S. aureus MMX MSSA 1.5 1 0.12 0.025 0.06 0.12 0.015 2490 S.aureus MMX MSSA 3 0.5 0.12 0.06 0.06 0.06 0.008 7907 S. aureus MMX MSSA2 1 0.12 0.06 0.12 0.12 0.015 7908 S. aureus MMX MRSA 3 1 0.09 0.06 0.060.06 0.008 2010 S. aureus MMX MRSA 2 1 0.12 0.03 0.12 0.06 0.0082011ATCC BAA-1756 S. aureus MMX MRSA 3 0.5 0.185 0.12 0.06 0.06 0.0083982 S. aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 4675ATCCBAA-1556 S. aureus MMX MRSA 1 1 0.25 0.12 0.06 0.06 0.015 5717 ATCC33591 S. aureus MMX MRSA 2.5 0.5 0.185 0.03 0.06 0.06 0.008 5985 S.aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 5999 S. aureus MMXMRSA 1.5 0.5 0.12 0.12 0.06 0.06 0.008 7899 S. aureus MMX MRSA 2 0.50.185 0.12 0.12 0.06 0.008 7900 S. aureus MMX MRSA 2 0.5 0.12 0.5 0.060.03 0.008 7901 S. aureus MMX MRSA 2 1 0.12 0.5 0.25 0.06 0.015 7902 S.aureus MMX MRSA 1.5 1 0.12 0.06 0.06 0.06 0.008 7903 S. aureus MMX hVISA1.5 4 0.25 0.5 0.5 0.25 0.03 4665 S. aureus MMX Mu3; hVISA 1.5 1 0.750.12 0.06 0.12 0.015 5989 S. aureus MMX Mu50; VISA 1.25 8 0.5 1 0.5 0.50.06 1723 S. aureus MMX VISA; 1.5 4 0.045 1 0.25 0.5 0.06 2124 DaptoNSS. aureus MMX VISA 1.5 4 0.12 0.25 0.5 0.12 0.03 4658 S. aureus MMX VISA2.5 4 0.09 1 0.12 0.12 0.03 4660 S. aureus MMX 100 MSSA 4 1 0.25 0.030.06 0.06 0.008 ATCC 29213 *LNZ and TGC values are average MICs from n =2 experiments; all others are n = 1 experiment. **In Figure 4, strainslisted here are arranged left to right in the bar plots.

S. aureus ATCC 29213 was included during the testing of S. aureus forpurposes of quality control (Clinical and Laboratory Standards Institute(CLSI). Performance Standards for Antimicrobial Susceptibility Testing:Twenty-Seventh Informational Supplement. CLSI document M100-S27. CLSI,950 West Valley Road, Suite 2500, Wayne, Pa. 19087 USA, 2017; CLSI.Methods for Dilution Antimicrobial Susceptibility Tests for BacteriaThat Grow Aerobically; Approved Standard-Tenth Edition. CLSI documentM07-A10. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa. 19087-1898USA, 2015).

A summary of the subset of MRSA strains is also provided in Table 5.

TABLE 5 MIC (μg/mL) #40 Organism Isolate No. Phenotype LNZ* VAN* TCG*ORI #5 TLV (RV40)* S. aureus MMX MRSA 3 1 0.09 0.06 0.06 0.06 0.008 2010S. aureus MMX MRSA 2 1 0.12 0.03 0.12 0.06 0.008 2011ATCC BAA-1756 S.aureus MMX MRSA 3 0.5 0.185 0.12 0.06 0.06 0.008 3982 S. aureus MMX MRSA1.5 1 0.12 0.06 0.06 0.06 0.008 4675ATCC BAA-1556 S. aureus MMX MRSA 1 10.25 0.12 0.06 0.06 0.015 5717 ATCC 33591 S. aureus MMX MRSA 2.5 0.50.185 0.03 0.06 0.06 0.008 5985 S. aureus MMX MRSA 1.5 0.5 0.12 0.120.06 0.06 0.008 5999 S. aureus MMX MRSA 1.5 0.5 0.12 0.12 0.06 0.060.008 7899 S. aureus MMX MRSA 2 0.5 0.185 0.12 0.12 0.06 0.008 7900 S.aureus MMX MRSA 2 0.5 0.12 0.5 0.06 0.03 0.008 7901 S. aureus MMX MRSA 21 0.12 0.5 0.25 0.06 0.015 7902 S. aureus MMX MRSA 1.5 1 0.12 0.06 0.060.06 0.008 7903 *LNZ and TGC values are average MICs from n = 2experiments; all others are n = 1 experiment. **In Figure 6, strainslisted here are arranged left to right in the bar plots.

With respect to the MRSA strains (Table 5), Compound 40 (RV40) was foundto be more active than the respective comparator drug by the factorsprovided in Table 6.

TABLE 6 RV40 activity Comparator as compared Drug to Comparator LNZ 214× VAN  86 × TGC  16 × ORI  17 × Compound 5  9 × TLV  6 ×

A summary of the subset of Gram Positive strains other than those of theS. aureus species is provided below in Table 7. Blank entries indicatethat the respective antibiotic was not tested against the respectiveorganism.

TABLE 7 MIC Organism Isolate No. Type LNZ VAN TGC ORI #5 TLV #40 S.epidermidis MMX 762 MRSE 2 2 0.06 0.25 0.12 0.12 0.008 (CoNS) S.epidermidis MMX 5145 MRSE 0.5 1 0.12 0.12 0.06 0.03 0.004 (CoNS) S.lugdenensis MMX 8724 — 0.5 0.5 0.06 ≤0.008 0.03 0.06 0.004 (CoNS) S.haemolyticus MMX 529 — 0.5 1 0.06 0.12 0.06 0.06 0.015 (CoNS) ATCC 29970S. hominis MMX 667 — 1 0.5 0.12 0.06 0.06 0.06 0.015 (CoNS) ATCC 27844E. faecalis MMX 101 VSE 2 2 0.06 ≤0.008 0.06 0.12 0.015 ATCC 29212 E.faecalis MMX 4176 — 4 1 0.12 0.03 — 0.25 0.03 E. faecalis MMX 1086 VanAVRE 2 >64 0.12 1 0.06 1 0.5 E. faecium MMX 4204 — 2 0.5 0.06 0.015 —0.06 0.004 E. faecium MMX 851 VanA VRE 2 >64 0.06 0.12 2 2 1 E. faeciumMMX 173 VanB VRE 4 >64 0.06 ≤0.008 0.12 0.06 0.008 S. pneumoniae MMX1195 PISP 1 0.25 0.06 ≤0.008 0.015 0.03 0.004 ATCC 49619 S. pneumoniaeMMX 747 — 1 0.12 0.03 ≤0.008 — 0.015 0.004 S. pneumoniae MMX 432 PRSP 10.25 0.03 ≤0.008 — 0.03 0.008 S. pyogenes MMX 404 — 2 0.25 0.015 2 —0.06 0.06 ATCC 19615 S. pyogenes MMX 946 ermR 1 0.25 0.015 0.25 0.0150.06 0.008 S. pyogenes MMX 8778 — 1 0.25 0.03 1 — 0.06 0.015 C.difficile MMX 4381 toxinAB- 1 0.25 0.18 1 0.06 0.12 0.06 ATCC 700057negative C. difficile MMX 4994 ribotype 027 — 0.25 0.03 0.5 0.06 0.120.06 ATCC BAA-1805 C. difficile MMX 5668 NAP1/027 — 1 0.03 2 0.5 0.120.12 ATCC BAA-1870 S. agalactiae MMX 427 — — 0.25 — 1 0.03 0.06 0.015ATCC 13813 S. agalactiae MMX 4088 — 1 0.25 0.03 0.12 0.015 0.06 0.008 S.agalactiae MMX 4115 erm^(R) 1 0.25 0.03 0.25 0.015 0.06 0.008 S.dysgalactiae MMX 5121 — 1 0.25 0.06 0.05 0.015 0.12 0.008 S.dysgalactiae MMX 5123 — 1 0.5 0.015 2 0.03 0.25 0.12 S. dysgalactiae MMX5124 — 1 0.25 0.12 1 0.015 0.03 0.015 S. anginosus MMX 1201 — 0.5 0.50.008 0.5 0.03 0.06 0.015 (AGS) ATCC 33397 S. constellatus MMX 5677 —0.5 0.25 0.03 ≤0.008 0.03 0.03 0.008 (AGS) S. mitis (MGS) MMX 1205 — —0.5 — 0.03 0.03 0.06 0.008 ATCC 49456 S. mitis (MGS) MMX 5798 — 0.5 0.250.03 0.25 0.015 −0.03 0.03 S. oralis (MGS) MMX 5821 — 1 0.25 0.06 ≤0.0080.03 0.06 0.015 C. perfringens MMX 8351 — — 0.5 0.12 0.015 0.06 0.0150.015 ATCC 13124 P. micros MMX 3546 — — 0.5 0.015 0.03 0.12 0.06 0.015P. anaerobius MMX 1208 — — 0.25 0.03 0.03 0.03 0.03 0.008 ATCC 27337 P.acnes MMX 7942 — — 0.25 0.03 ≤0.008 0.06 0.03 0.008 ATCC 6919 P. acnesMMX 7946 — — 0.25 0.03 ≤0.008 0.06 0.015 0.008 ATCC 11827 E. lenta MMX1287 — — — 0.25 — 0.12 — — ATCC 43055

Test Media.

The medium employed for the MIC assay was cation-adjusted Mueller-HintonBroth (MHBII; BD; Lot No. 6117994), excluding C. difficile which weretested in supplemented Brucella Broth (SBB). For Streptococcus isolates,the MHBII was supplemented with 3% Laked Horse Blood (ClevelandScientific; Bath, Ohio; Lot No. 333835). For testing C. difficile,Brucella Broth (BD; Lot No. 6155858) was supplemented with vitamin K(Sigma, St. Louis, Mo.; Lot No. 108K1088), hemin (Sigma; Lot No.SLB14685V), and 5% Laked Horse Blood. Test media was prepared fresh oneach day of testing and was supplemented with 0.002% polysorbate-80(v/v) for the testing of telavancin per CLSI (Clinical and LaboratoryStandards Institute (CLSI). Performance Standards for AntimicrobialSusceptibility Testing: Twenty-Seventh Informational Supplement. CLSIdocument M100-S27. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pa.19087 USA, 2017; CLSI. Methods for Dilution Antimicrobial SusceptibilityTests for Bacteria That Grow Aerobically; Approved Standard—TenthEdition. CLSI document M07-A10. CLSI, 950 West Valley Road, Suite 2500,Wayne, Pa. 19087-1898 USA, 2015) and for the testing of oritavancin,Compound 40 and Compound 5.

Test Procedure.

MIC values were determined using a broth microdilution proceduredescribed by CLSI (Clinical and Laboratory Standards Institute (CLSI).Performance Standards for Antimicrobial Susceptibility Testing:Twenty-Seventh Informational Supplement. CLSI document M100-S27. CLSI,950 West Valley Road, Suite 2500, Wayne, Pa. 19087 USA, 2017). Automatedliquid handlers (Multidrop 384, Labsystems, Helsinki, Finland; Biomek2000 and Biomek FX, Beckman Coulter, Fullerton Calif.) were used toconduct serial dilutions and liquid transfers.

To prepare the drug mother plates, which would provide the serial drugdilutions for the replicate daughter plates, the wells of columns 2-12of standard 96-well microdilution plates (Costar 3795) were filled with150 μL of the designated diluent for each row of drug. The test articlesand comparator compounds (300 μL at 100× the highest concentration to betested) were dispensed into the appropriate wells in column 1. TheBiomek 2000 was then used to make 2-fold serial dilutions in the motherplates from column 1 through column 11. The wells of Column 12 containedno drug and served as the organism growth control wells for the assay.

The daughter plates were loaded with 190 μL per well of the appropriatetest medium containing 0.002% polysorbate-80 (v/v) for telavancin,oritavancin, Compound 40, and Compound 5, using the Multidrop 384. Thedaughter plates were prepared on the Biomek FX instrument whichtransferred 2 μL of drug solution from each well of a mother plate tothe corresponding well of each daughter plate in a single step. Thedaughter plates for C. difficile were placed in the anaerobe chamber andallowed to reduce for one hour prior to inoculation.

A standardized inoculum of each organism was prepared per CLSI methods(CLSI. Methods for Dilution Antimicrobial Susceptibility Tests forBacteria That Grow Aerobically;

Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI, 950 WestValley Road, Suite 2500, Wayne, Pa. 19087-1898 USA, 2015). Bacterialsuspensions were prepared in MHBII (or in the case of C. difficile SBBwithout blood) to equal the turbidity of a 0.5 McFarland standard. The0.5 McFarland suspensions were further diluted 1:20 (or in the case ofC. difficile, 1:10) in the appropriate test medium. The inoculum foreach organism was dispensed into sterile reservoirs (Beckman Coulter372788), and the Biomek 2000 was used to deliver 10 μL of standardizedinoculum into each well resulting in a final test concentration ofapproximately 5×10⁵ CFU/mL. Daughter plates were placed on the Biomek2000 work surface reversed so that inoculation took place from low tohigh drug concentration. For C. difficile, inoculum preparation and theinoculation of the daughter plates was carried out by hand in theanaerobe chamber.

Plates were stacked 3 high, covered with a lid on the top plate, placedin plastic bags, and incubated at 35° C. in ambient atmosphere forapproximately 18-20 hr for telavancin, Compound 40, Compound 5,oritavancin, linezolid, and tigecycline, or 24 hr for vancomycin withthe exception of C. difficile plates which were incubated at 35° C.anaerobically for 48 h. Following incubation, the microplates wereremoved from the incubator and viewed from the bottom using a plateviewer. For each of the test compounds, an un-inoculated solubilitycontrol plate for each test medium was observed for evidence of drugprecipitation. The MIC was read and recorded as the lowest concentrationof drug that inhibited visible growth. For linezolid, pinpoint trailingwas ignored when reading the MIC per CLSI (CLSI. Methods for DilutionAntimicrobial Susceptibility Tests for Bacteria That Grow Aerobically;Approved Standard-Tenth Edition. CLSI document M07-A10. CLSI, 950 WestValley Road, Suite 2500, Wayne, Pa. 19087-1898 USA, 2015).

Results

No precipitation was observed for the comparators during the assay withthe un-inoculated solubility controls. Some precipitation was noted forCompound 40 and Compound 5 at the top concentration tested (64 μg/mL) inMHBII with blood and supplemented Brucella broth, and for Compound 40(RV40) in HTM. However, this precipitation did not interfere with thereading of MICs. The MICs of comparators against ATCC quality controlorganisms were within the established CLSI QC ranges (CLSI. PerformanceStandards for Antimicrobial Susceptibility Testing; Twenty-seventhInformational Supplement. CLSI document M100-S27. CLSI, 940 West ValleyRoad, Suite 1400, Wayne, Pa. 19087-1898 USA, 2017.), thus validating theassay.

The observed MIC values for the S. aureus strains against the variousantibiotics is provided at Tables 3-5. These data are also provided atFIGS. 6 and 7. Data for the 12 MRSA strains are provided at Tables 4-5,and FIGS. 8 and 9.

The observed MIC values for the Gram positive strains other than S.aureus against the various antibiotics is provided at Table 6. Compound40 was the most potent compound across the evaluated Streptococci,Enterococci, and C. difficile test isolates. The activity observed withCompound 40 was 5-fold greater than that of the telavancin, a trendconsistent with the data observed with S. aureus where Compound 40 was3-fold great than that of telavancin (Table 1). Both telavancin andCompound 40 had potent activity against vancomycin-resistant enterococci(VRE) though MIC values for VRE were elevated relative tovancomycin-susceptible enterococci (VSE).

Example 12—MRSA 1556 Biofilm Eradication

Vancomycin (Vanc), telavancin (TLV), oritivancin (ORI) and RV40(compound of Formula (I) or (II) where R¹ is (CH₂)—NH—(CH₂)₉—CH₃, R² isOH, R³ and R⁴ are H and X is O) were tested for their ability toeradicate MRSA 1556 biofilm.

For biofilm development, empty 96-well plates or cystic fibrosisbronchial epithelial (CFBE) cells that were seeded in a 24-well platewere inoculated with MRSA 1556 overnight culture for 6 h followed by 16h antibiotic treatment. After 16 h incubation, planktonic bacteria wereremoved and biofilm was disrupted by scrapping method and collected forCFU count. The results are provided in FIG. 10 (plastic biofilm) andFIG. 11 (cell biofilm). RV40 killed MRSA 1556 biofilm that formed onplastic significantly at 0.3-10 μg/ml compared to telavancin andvancomycin (FIG. 10). RV40 was more potent to kill MRSA 1556 biofilmdeveloped in a co-culture with CFBE cells compared to vancomycin,telavancin and oritavancin with >3 log CFU/ml reduction at 20 μg/ml(FIG. 11).

Example 13—In Vivo Activity of Glycopeptide Agents Against MRSAOrganisms

Male Sprague Dawley rats (179-200 g) were rendered neutropenic through aseries of cyclophosphamide injections (IP) at 150 mg/kg (Day −4) and 100mg/kg (Day −1). They were then challenged with Methicillin-ResistantStaphylococcus aureus (MRSA) (ATCC-BAA-1556; TPPS 1062) at 8 log 10 viaintranasal (IN) instillation on study Day 0.

Rats were treated with vehicle control (bicine; pH 9.2) or RV40(compound 40) (in bicine; pH 9.2) via nebulization using CH Technologies12 Port Module Oral-Nasal Aerosol and Respiratory Exposure Systems(ONARES) connected to an Aeroneb Pro nebulizer at 12 h and 24 hpost-challenge. At 36 hours, post-challenge lungs were collected for CFUenumeration. The results are shown in FIG. 12.

For the data reported in FIG. 13, At 36 h, post-challenge lungs werecollected for CFU enumeration. Drugs that were nebulized were done usingthe same procedures described for the data in FIG. 12. Results arelisted as the Δ Log reduction in lung CFU versus control (FIG. 13).

The same animal model from FIG. 12 was used to acquire the data in FIG.14 regarding the dose response of inhaled RV40 in reducing lung MRSACFUs. Again, animals were treated with the drug at 12 h and 24 hpost-challenge. At 36 hours, post-challenge lungs were collected for CFUenumeration. Here, animals were dosed with RV40 at body-weight targetsof 1, 2, 5, and 10 mg/kg using the same nebulization proceduresdescribed for the data in FIG. 12. Results are listed as the Δ Logreduction in lung CFU versus control (FIG. 14). Data is plotted as meanand error is SEM.

The same animal model from FIG. 12 was used to acquire the data in FIG.15 regarding prophylactic dosing of inhaled RV40 to reduce lung MRSACFUs. Here, animals were administered single doses of nebulized inhaledRV40 (10 mg/kg body weight target) at 7, 5, 3, and 1 days beforebacterial challenge and at 0.5 days after bacterial challenge. At 36hours post-challenge lungs were collected for CFU enumeration. Dosingwas done using the same nebulization procedures described for the datain FIG. 12. The results are provided at FIG. 15. Data is plotted asgeometric mean with 95% CI. Statistics based on one-way ANOVA (p=0.001)with post-hoc Bonferroni multiple comparison test. N=11 for treatmentgroups on Days −7, −5, −3, −1, n=10 for Day +0.5, and n=8 for control.

All, documents, patents, patent applications, publications, productdescriptions, and protocols which are cited throughout this applicationare incorporated herein by reference in their entireties for allpurposes.

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Modifications and variationof the above-described embodiments of the invention are possible withoutdeparting from the invention, as appreciated by those skilled in the artin light of the above teachings. It is therefore understood that, withinthe scope of the claims and their equivalents, the invention may bepracticed otherwise than as specifically described.

1. (canceled)
 2. A method for treating a bacterial pulmonary infectionin a patient in need thereof, comprising administering to the lungs of apatient via a nebulizer, metered dose inhaler or a dry powder inhaler, acomposition comprising an effective amount of a compound of Formula(II), or a pharmaceutically acceptable salt thereof:

wherein: R¹ is C₁-C₁₈ linear alkyl, C₁-C₁₈ branched alkyl,R⁵—Y—R⁶—(Z)_(n), or

R² is —OH or —NH—(CH₂)_(q)—R⁷; R³ is H or

R⁴ is H or CH₂NH—CH₂—PO₃H₂; n is 1 or 2; q is 1, 2, 3, 4, or 5; X is O,S, NH or H₂; each Z is independently selected from hydrogen, aryl,cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; R⁵ and R⁶ areindependently selected from the group consisting of alkylene, alkenyleneand alkynylene, wherein the alkylene, alkenylene and alkynylene groupsare optionally substituted with from 1 to 3 substituents selected fromthe group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl,thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy,substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl R⁷ is —N(CH₂)₂;—N(CH₂)₃; or

Y is independently selected from the group consisting of oxygen, sulfur,—S—S—, —NR⁸—, —S(O)—, —SO₂—, —OSO₂—, —NR⁸SO₂—, —SO₂NR⁸—, —SO₂O—,—P(O)(OR⁸)O—, —P(O)(OR⁸)NR—, —OP(O)(OR⁸)O—, —OP(O)(OR⁸)NR⁸—,—NR⁸C(O)NR⁸—, and —NR⁸SO₂NR⁸—; and each R⁸ is independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heteroaryl and heterocyclic.
 3. The method of claim 2, wherein R³ is H.4. The method of claim 2, wherein R³ is


5. The method of claim 3, wherein R⁴ is H.
 6. The method of claim 3,wherein R⁴ is CH₂—NH—CH₂—PO₃H₂.
 7. The method of claim 1, wherein X isO. 8-12. (canceled)
 13. The method of claim 1, wherein R¹ isR⁵—Y—R⁶—(Z)_(n) and Y is —NH—.
 14. (canceled)
 15. The method of claim 7,wherein R¹ is (CH₂)₂—Y—R⁶—(Z)_(n). 16-19. (canceled)
 20. The method ofclaim 13, wherein R¹ is R⁵—Y—(CH₂)₁₀—(Z).
 21. The method of claim 20,wherein (Z)_(n) is H and R⁴ is H.
 22. The method of claim 1, wherein R²is OH, R⁴ is H, Y is —NH—, and (Z)_(n) is H. 23-24. (canceled)
 25. Themethod of claim 1, wherein R¹ is n-decyl. 26-39. (canceled)
 40. Themethod of claim 1, wherein R¹ is (CH₂)₂—NH—(CH₂)₉—CH₃. 41-43. (canceled)44. The method of claim 40, wherein R² is OH. 45-80. (canceled)
 81. Themethod of claim 1, wherein the bacterial infection is a Gram positivebacterial pulmonary infection. 82-83. (canceled)
 84. The method of claim81, wherein the Gram-positive bacterial pulmonary infection is aStaphylococcus pulmonary infection. 85-86. (canceled)
 87. The method ofclaim 84, wherein the Staphylococcus pulmonary infection is aStaphylococcus aureus (S. aureus) pulmonary infection.
 88. The method ofclaim 87, wherein the S. aureus pulmonary infection is amethicillin-resistant S. aureus (MRSA) pulmonary infection.
 89. Themethod of claim 87, wherein the S. aureus pulmonary infection is amethicillin-sensitive S. aureus (MSSA) pulmonary infection. 90-117.(canceled)
 118. The method of claim 1, wherein the patient is a cysticfibrosis patient. 119-122. (canceled)